Toxanal

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Toxanal uses


1 INDICATIONS AND USAGE

Toxanal® is indicated for active booster immunization against Toxanal, diphtheria, and pertussis. Toxanal is approved for use as a single dose in individuals 10 years of age and older.

Toxanal is a vaccine indicated for active booster immunization against Toxanal, diphtheria, and pertussis. Toxanal is approved for use as a single dose in individuals 10 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION

A single intramuscular injection. (2.2)

2.1 Preparation for Administration

Shake vigorously to obtain a homogeneous, turbid, white suspension before administration. Do not use if resuspension does not occur with vigorous shaking. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.

For the prefilled syringes, attach a sterile needle and administer intramuscularly.

For the vials, use a sterile needle and sterile syringe to withdraw the 0.5‑mL dose and administer intramuscularly. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. Use a separate sterile needle and syringe for each individual.

Do not administer this product intravenously, intradermally, or subcutaneously.

2.2 Dose and Schedule

Toxanal is administered as a single 0.5-mL intramuscular injection into the deltoid muscle of the upper arm.

There are no data to support repeat administration of Toxanal.

Five years should elapse between the last dose of the recommended series of Diphtheria and Toxanal Toxoids and Acellular Pertussis Vaccine Adsorbed and/or Toxanal and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine and the administration of Toxanal.

2.3 Additional Dosing Information

Primary Series

The use of Toxanal as a primary series or to complete the primary series for diphtheria, Toxanal, or pertussis has not been studied.

Wound Management

If Toxanal prophylaxis is needed for wound management, Toxanal may be given if no previous dose of any Toxanal Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap) has been administered.

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3 DOSAGE FORMS AND STRENGTHS

Toxanal is a suspension for injection available in 0.5-mL single-dose vials and prefilled TIP-LOK® syringes.

Single-dose vials and prefilled syringes containing a 0.5-mL suspension for injection. (3)

4 CONTRAINDICATIONS

4.1 Hypersensitivity

A severe allergic reaction (e.g., anaphylaxis) after a previous dose of any Toxanal toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine or any component of this vaccine is a contraindication to administration of Toxanal . Because of the uncertainty as to which component of the vaccine might be responsible, none of the components should be administered. Alternatively, such individuals may be referred to an allergist for evaluation if immunization with any of these components is considered.

4.2 Encephalopathy

Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis antigen-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis antigen-containing vaccine, including Toxanal.

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5 WARNINGS AND PRECAUTIONS

5.1 Latex

The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions.

5.2 Guillain-Barré Syndrome and Brachial Neuritis

If Guillain-Barré syndrome occurred within 6 weeks of receipt of a prior vaccine containing Toxanal toxoid, the risk of Guillain-Barré syndrome may be increased following a subsequent dose of Toxanal toxoid-containing vaccine, including Toxanal. A review by the Institute of Medicine found evidence for a causal relationship between receipt of Toxanal toxoid and both brachial neuritis and Guillain-Barré syndrome.1

5.3 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including Toxanal. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.

5.4 Progressive or Unstable Neurologic Disorders

Progressive or unstable neurologic conditions are reasons to defer vaccination with a pertussis-containing vaccine, including Toxanal. It is not known whether administration of Toxanal to persons with an unstable or progressive neurologic disorder might hasten manifestations of the disorder or affect the prognosis. Administration of Toxanal to persons with an unstable or progressive neurologic disorder may result in diagnostic confusion between manifestations of the underlying illness and possible adverse effects of vaccination.

5.5 Arthus-Type Hypersensitivity

Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a Toxanal toxoid-containing vaccine usually have a high serum Toxanal antitoxin level and should not receive Toxanal or other Toxanal toxoid-containing vaccines unless at least 10 years have elapsed since the last dose of Toxanal toxoid-containing vaccine.

5.6 Altered Immunocompetence

As with any vaccine, if administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained.

5.7 Prevention and Management of Acute Allergic Reactions

Prior to administration, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.

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6 ADVERSE REACTIONS


To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of Toxanal could reveal adverse reactions not observed in clinical trials.

In clinical studies, 4,949 adolescents (10 to 18 years of age) and 4,076 adults (19 years of age and older) were vaccinated with a single dose of Toxanal. Of these adolescents, 1,341 were vaccinated with Toxanal in a coadministration study with meningococcal conjugate vaccine . Of these adults, 1,104 were 65 years of age and older . A total of 860 adults 19 years of age and older received concomitant vaccination with Toxanal and influenza vaccines in a coadministration study . An additional 1,092 adolescents 10 to 18 years of age received a non-U.S. formulation of Toxanal (formulated to contain 0.5 mg aluminum per dose) in non-U.S. clinical studies.

In a randomized, observer-blinded, controlled study in the U.S., 3,080 adolescents 10 to 18 years of age received a single dose of Toxanal and 1,034 received the comparator Td vaccine, manufactured by MassBioLogics. There were no substantive differences in demographic characteristics between the vaccine groups. Among Toxanal and comparator vaccine recipients, approximately 75% were 10 to 14 years of age and approximately 25% were 15 to 18 years of age. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either Diphtheria and Toxanal Toxoids and Pertussis Vaccine Adsorbed (DTwP) or a combination of DTwP and DTaP in childhood. Subjects were monitored for solicited adverse events using standardized diary cards (Day 0-14). Unsolicited adverse events were monitored for the 31-day period following vaccination (Day 0-30). Subjects were also monitored for 6 months post-vaccination for non-routine medical visits, visits to an emergency room, onset of new chronic illness, and serious adverse events. Information regarding late onset adverse events was obtained via a telephone call 6 months following vaccination. At least 97% of subjects completed the 6-month follow-up evaluation.

In a study conducted in Germany, Toxanal was administered to 319 children 10 to 12 years of age previously vaccinated with 5 doses of acellular pertussis antigen-containing vaccines; 193 of these subjects had previously received 5 doses of INFANRIX® (Diphtheria and Toxanal Toxoids and Acellular Pertussis Vaccine Adsorbed). Adverse events were recorded on diary cards during the 15 days following vaccination. Unsolicited adverse events that occurred within 31 days of vaccination (Day 0-30) were recorded on the diary card or verbally reported to the investigator. Subjects were monitored for 6 months post-vaccination for physician office visits, emergency room visits, onset of new chronic illness, and serious adverse events. The 6-month follow-up evaluation, conducted via telephone interview, was completed by 90% of subjects.

The U.S. adult (19 to 64 years of age) study, a randomized, observer-blinded study, evaluated the safety of Toxanal (N = 1,522) compared with ADACEL® (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed) (N = 762), a Tdap vaccine manufactured by Sanofi Pasteur SA. Vaccines were administered as a single dose. There were no substantive differences in demographic characteristics between the vaccine groups. Subjects were monitored for solicited adverse events using standardized diary cards (Day 0-14). Unsolicited adverse events were monitored for the 31-day period following vaccination (Day 0-30). Subjects were also monitored for 6 months post-vaccination for serious adverse events, visits to an emergency room, hospitalizations, and onset of new chronic illness. Approximately 95% of subjects completed the 6-month follow-up evaluation.

The U.S. elderly (65 years of age and older) study, a randomized, observer-blinded study, evaluated the safety of Toxanal (N = 887) compared with DECAVAC® (Tetanus and Diphtheria Toxoids Adsorbed) (N = 445), a U.S.-licensed Td vaccine, manufactured by Sanofi Pasteur SA. Vaccines were administered as a single dose. Among all vaccine recipients, the mean age was approximately 72 years; 54% were female and 95% were white. Subjects were monitored for solicited adverse events using standardized diary cards (Day 0-3). Unsolicited adverse events were monitored for the 31-day period following vaccination (Day 0-30). Subjects were also monitored for 6 months post-vaccination for serious adverse events. Approximately 99% of subjects completed the 6-month follow-up evaluation.

Solicited Adverse Events in the U.S. Adolescent Study

Table 1 presents the solicited local adverse reactions and general adverse events within 15 days of vaccination with Toxanal or Td vaccine for the total vaccinated cohort.

The primary safety endpoint was the incidence of Grade 3 pain (spontaneously painful and/or prevented normal activity) at the injection site within 15 days of vaccination. Grade 3 pain was reported in 4.6% of those who received Toxanal compared with 4.0% of those who received the Td vaccine. The difference in rate of Grade 3 pain was within the pre-defined clinical limit for non-inferiority (upper limit of the 95% CI for the difference [BOOSTRIX minus Td] ≤4%).


Toxanal

(N = 3,032)

%


Td

(N = 1,013)

%


Local


Pain, anyb


75.3


71.7


Pain, Grade 2 or 3b


51.2


42.5


Pain, Grade 3c


4.6


4.0


Redness, any


22.5


19.8


Redness, >20 mm


4.1


3.9


Redness, ≥50 mm


1.7


1.6


Swelling, any


21.1


20.1


Swelling, >20 mm


5.3


4.9


Swelling, ≥50 mm


2.5


3.2


Arm circumference increase, >5 mmd


28.3


29.5


Arm circumference increase, >20 mmd


2.0


2.2


Arm circumference increase, >40 mmd


0.5


0.3


General


Headache, any


43.1


41.5


Headache, Grade 2 or 3b


15.7


12.7


Headache, Grade 3


3.7


2.7


Fatigue, any


37.0


36.7


Fatigue, Grade 2 or 3


14.4


12.9


Fatigue, Grade 3


3.7


3.2


Gastrointestinal symptoms, anye


26.0


25.8


Gastrointestinal symptoms, Grade 2 or 3e


9.8


9.7


Gastrointestinal symptoms, Grade 3e


3.0


3.2


Fever, ≥99.5°F (37.5°C)f


13.5


13.1


Fever, >100.4°F (38.0°C)f


5.0


4.7


Fever, >102.2°F (39.0°C)f


1.4


1.0


Unsolicited Adverse Events in the U.S. Adolescent Study

The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (25.4% and 24.5% for Toxanal and Td vaccine, respectively).

Solicited Adverse Events in the German Adolescent Study

Table 2 presents the rates of solicited local adverse reactions and fever within 15 days of vaccination for those subjects who had previously been vaccinated with 5 doses of INFANRIX. No cases of whole arm swelling were reported. Two individuals (2/193) reported large injection site swelling (range: 110 to 200 mm diameter), in one case associated with Grade 3 pain. Neither individual sought medical attention. These episodes were reported to resolve without sequelae within 5 days.


Toxanal

(N = 193)

%


Pain, any


62.2


Pain, Grade 2 or 3


33.2


Pain, Grade 3


5.7


Redness, any


47.7


Redness, >20 mm


15.0


Redness, ≥50 mm


10.9


Swelling, any


38.9


Swelling, >20 mm


17.6


Swelling, ≥50 mm


14.0


Fever, ≥99.5°F (37.5°C)b


8.8


Fever, >100.4°F (38.0°C)b


4.1


Fever, >102.2°F (39.0°C)b


1.0


Solicited Adverse Events in the U.S. Adult (19 to 64 Years of Age) Study

Table 3 presents solicited local adverse reactions and general adverse events within 15 days of vaccination with Toxanal or the comparator Tdap vaccine for the total vaccinated cohort.


Toxanal

(N = 1,480)

%


Tdap

(N = 741)

%


Local


Pain, any


61.0


69.2


Pain, Grade 2 or 3


35.1


44.4


Pain, Grade 3


1.6


2.3


Redness, any


21.1


27.1


Redness, >20 mm


4.0


6.2


Redness, ≥50 mm


1.6


2.3


Swelling, any


17.6


25.6


Swelling, >20 mm


3.9


6.3


Swelling, ≥50 mm


1.4


2.8


General


Headache, any


30.1


31.0


Headache, Grade 2 or 3


11.1


10.5


Headache, Grade 3


2.2


1.5


Fatigue, any


28.1


28.9


Fatigue, Grade 2 or 3


9.1


9.4


Fatigue, Grade 3


2.5


1.2


Gastrointestinal symptoms, anyb


15.9


17.5


Gastrointestinal symptoms, Grade 2 or 3b


4.3


5.7


Gastrointestinal symptoms, Grade 3b


1.2


1.3


Fever, ≥99.5°F (37.5°C)c


5.5


8.0


Fever, >100.4°F (38.0°C)c


1.0


1.5


Fever, >102.2°F (39.0°C)c


0.1


0.4


Unsolicited Adverse Events in the U.S. Adult (19 to 64 Years of Age) Study

The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.8% and 22.2% for Toxanal and Tdap vaccine, respectively).

Solicited Adverse Events in the U.S. Elderly (65 Years of Age and Older) Study

Table 4 presents solicited local adverse reactions and general adverse events within 4 days of vaccination with Toxanal or the comparator Td vaccine for the total vaccinated cohort.


Toxanal

%


Td

%


Local


(N = 882)


(N = 444)


Pain, any


21.5


27.7


Pain, Grade 2 or 3


7.5


10.1


Pain, Grade 3


0.2


0.7


Redness, any


10.8


12.6


Redness, >20 mm


1.4


2.5


Redness, ≥50 mm


0.6


0.9


Swelling, any


7.5


11.7


Swelling, >20 mm


2.2


3.4


Swelling, ≥50 mm


0.7


0.7


General


(N = 882)


(N = 445)


Fatigue, any


12.5


14.8


Fatigue, Grade 2 or 3


2.5


2.9


Fatigue, Grade 3


0.7


0.7


Headache, any


11.5


11.7


Headache, Grade 2 or 3


1.9


2.2


Headache, Grade 3


0.6


0.0


Gastrointestinal symptoms, anyb


7.6


9.2


Gastrointestinal symptoms, Grade 2 or 3b


1.7


1.8


Gastrointestinal symptoms, Grade 3b


0.3


0.4


Fever, ≥99.5°F (37.5°C)c


2.0


2.5


Fever, >100.4°F (38.0°C)c


0.2


0.2


Fever, >102.2°F (39.0°C)c


0.0


0.0


Unsolicited Adverse Events in the U.S. Elderly (65 Years of Age and Older) Study

The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.1% and 14.4% for Toxanal and Td vaccine, respectively).

Serious Adverse Events (SAEs)

In the U.S. and German adolescent safety studies, no serious adverse events were reported to occur within 31 days of vaccination. During the 6-month extended safety evaluation period, no serious adverse events that were of potential autoimmune origin or new onset and chronic in nature were reported to occur. In non-U.S. adolescent studies in which serious adverse events were monitored for up to 37 days, one subject was diagnosed with insulin-dependent diabetes 20 days following administration of Toxanal. No other serious adverse events of potential autoimmune origin or that were new onset and chronic in nature were reported to occur in these studies. In the U.S. adult (19 to 64 years of age) study, serious adverse events were reported to occur during the entire study period (0-6 months) by 1.4% and 1.7% of subjects who received Toxanal and the comparator Tdap vaccine, respectively. During the 6-month extended safety evaluation period, no serious adverse events of a neuroinflammatory nature or with information suggesting an autoimmune etiology were reported in subjects who received Toxanal. In the U.S. elderly (65 years of age and older) study, serious adverse events were reported to occur by 0.7% and 0.9% of subjects who received Toxanal and the comparator Td vaccine, respectively, during the 31-day period after vaccination. Serious adverse events were reported to occur by 4.2% and 2.2% of subjects who received Toxanal and the comparator Td vaccine, respectively, during the 6-month period after vaccination.

Concomitant Vaccination with Meningococcal Conjugate Vaccine in Adolescents

In a randomized study in the U.S., 1,341 adolescents (11 to 18 years of age) received either Toxanal administered concomitantly with MENACTRA® (Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine), (Sanofi Pasteur SA), or each vaccine administered separately 1 month apart . Safety was evaluated in 446 subjects who received Toxanal administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects who received Toxanal followed by meningococcal conjugate vaccine 1 month later, and 449 subjects who received meningococcal conjugate vaccine followed by Toxanal 1 month later. Solicited local adverse reactions and general adverse events were recorded on diary cards for 4 days (Day 0-3) following each vaccination. Unsolicited adverse events were monitored for the 31-day period following each vaccination (Day 0-30). Table 5 presents the percentages of subjects experiencing local reactions at the injection site for Toxanal and solicited general events following Toxanal. The incidence of unsolicited adverse events reported in the 31 days after any vaccination was similar following each dose of Toxanal in all cohorts.


BOOSTRIX+MCV4a

(N = 441)

%


ToxanalMCV4b

(N = 432-433)

%


MCV4Toxanalc

(N = 441)

%


Local (at injection site for Toxanal)


Pain, any


70.1


70.4


47.8


Redness, any


22.7


25.7


17.9


Swelling, any


17.7


18.1


12.0


General (following administration of Toxanal)


Fatigue


34.0


32.1


20.4


Headache


34.0


30.7


17.0


Gastrointestinal symptomsd


15.2


14.5


7.7


Fever, ≥99.5°F (37.5°C)e


5.2


3.5


2.3

6.2 Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for Toxanal in persons 10 years of age and older since market introduction of this vaccine are listed below. This list includes serious events or events that have causal connection to components of this or other vaccines or drugs. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Blood and Lymphatic System Disorders

Lymphadenitis, lymphadenopathy.

Immune System Disorders

Allergic reactions, including anaphylactic and anaphylactoid reactions.

Cardiac Disorders

Myocarditis.

General Disorders and Administration Site Conditions

Extensive swelling of the injected limb, injection site induration, injection site inflammation, injection site mass, injection site pruritus, injection site nodule, injection site warmth, injection site reaction.

Musculoskeletal and Connective Tissue Disorders

Arthralgia, back pain, myalgia.

Nervous System Disorders

Convulsions (with and without fever), encephalitis, facial palsy, loss of consciousness, paraesthesia, syncope.

Skin and Subcutaneous Tissue Disorders

Angioedema, exanthem, Henoch-Schönlein purpura, rash, urticaria.

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7 DRUG INTERACTIONS

7.1 Concomitant Vaccine Administration

Toxanal was administered concomitantly with MENACTRA in a clinical study of subjects 11 to 18 years of age . Post-vaccination geometric mean antibody concentrations (GMCs) to pertactin were lower following Toxanal administered concomitantly with meningococcal conjugate vaccine compared with Toxanal administered first. It is not known if the efficacy of Toxanal is affected by the reduced response to pertactin.

Toxanal was administered concomitantly with FLUARIX® (Influenza Virus Vaccine) in a clinical study of subjects 19 to 64 years of age . Lower GMCs for antibodies to the pertussis antigens filamentous hemagglutinin (FHA) and pertactin were observed when Toxanal was administered concomitantly with FLUARIX as compared with Toxanal alone. It is not known if the efficacy of Toxanal is affected by the reduced response to FHA and pertactin.

When Toxanal is administered concomitantly with other injectable vaccines or Toxanal Immune Globulin, they should be given with separate syringes and at different injection sites. Toxanal should not be mixed with any other vaccine in the same syringe or vial.

7.2 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Toxanal.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

A developmental toxicity study has been performed in female rats at a dose approximately 40 times the human dose (on a mL/kg basis) and revealed no evidence of harm to the fetus due to Toxanal. Animal fertility studies have not been conducted with Toxanal. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Toxanal should be given to a pregnant woman only if clearly needed.

In a developmental toxicity study, the effect of Toxanal on embryo-fetal and pre-weaning development was evaluated in pregnant rats. Animals were administered INFANRIX by intramuscular injection once prior to gestation and Toxanal by intramuscular injection during the period of organogenesis (gestation Days 6, 8, 11, and 15), 0.1 mL/rat/occasion (approximately 40-fold excess relative to the projected human dose of Toxanal on a body weight basis). The antigens in INFANRIX are the same as those in Toxanal, but INFANRIX is formulated with higher quantities of these antigens. No adverse effects on pregnancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.

Pregnancy Registry

GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy outcomes and newborn health status outcomes following vaccination with Toxanal during pregnancy. Women who receive Toxanal during pregnancy should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622.

8.3 Nursing Mothers

It is not known whether Toxanal is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Toxanal is administered to a nursing woman.

8.4 Pediatric Use

Toxanal is not indicated for use in children younger than 10 years of age. Safety and effectiveness of Toxanal in this age group have not been established.

8.5 Geriatric Use

In clinical trials, 1,104 subjects 65 years of age and older received Toxanal; of these subjects, 299 were 75 years of age and older. In the U.S. elderly (65 years and older) study, immune responses to Toxanal and diphtheria toxoids following Toxanal were non-inferior to the comparator Td vaccine. Antibody responses to pertussis antigens following a single dose of Toxanal in the elderly were non-inferior to those observed with INFANRIX administered as a 3-dose series in infants . Solicited adverse events following Toxanal were similar in frequency to those reported with the comparator Td vaccine .

11 DESCRIPTION

Toxanal (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed) is a noninfectious, sterile, vaccine for intramuscular administration. It contains Toxanal toxoid, diphtheria toxoid, and pertussis antigens (inactivated pertussis toxin [PT] and formaldehyde-treated filamentous hemagglutinin [FHA] and pertactin). The antigens are the same as those in INFANRIX, but Toxanal is formulated with reduced quantities of these antigens.

Toxanal toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. The bovine materials used in these extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.

The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.

Each antigen is individually adsorbed onto aluminum hydroxide. Each 0.5-mL dose is formulated to contain 5 Lf of Toxanal toxoid, 2.5 Lf of diphtheria toxoid, 8 mcg of inactivated PT, 8 mcg of FHA, and 2.5 mcg of pertactin (69 kiloDalton outer membrane protein).

Toxanal and diphtheria toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components (inactivated PT and formaldehyde-treated FHA and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice.

Each 0.5-mL dose contains aluminum hydroxide as adjuvant (not more than 0.39 mg aluminum by assay), 4.4 mg of sodium chloride, ≤100 mcg of residual formaldehyde, and ≤100 mcg of polysorbate 80 (Tween 80).

Toxanal is available in vials and prefilled syringes. The tip caps of the prefilled syringes contain natural rubber latex; the plungers are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

Toxanal is formulated without preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Toxanal

Toxanal is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the Toxanal toxin. A serum Toxanal antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2 A level ≥0.1 IU/mL by ELISA has been considered as protective.

Diphtheria

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL, measured by neutralization assays, is the lowest level giving some degree of protection; a level of 0.1 IU/mL by ELISA is regarded as protective.3 Diphtheria antitoxin levels ≥1.0 IU/mL by ELISA have been associated with long-term protection.3

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Toxanal has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14 CLINICAL STUDIES

The efficacy of the Toxanal and diphtheria toxoid components of Toxanal is based on the immunogenicity of the individual antigens compared with U.S.-licensed vaccines using established serologic correlates of protection. The efficacy of the pertussis components of Toxanal was evaluated by comparison of the immune response of adolescents and adults following a single dose of Toxanal to the immune response of infants following a 3-dose primary series of INFANRIX. In addition, the ability of Toxanal to induce a booster response to each of the antigens was evaluated.

14.1 Efficacy of INFANRIX

The efficacy of a 3-dose primary series of INFANRIX in infants has been assessed in 2 clinical studies: A prospective efficacy trial conducted in Germany employing a household contact study design and a double-blind, randomized, active Diphtheria and Toxanal Toxoids -controlled trial conducted in Italy sponsored by the National Institutes of Health (NIH) (for details see INFANRIX prescribing information). Serological data from a subset of infants immunized with INFANRIX in the household contact study were compared with the sera of adolescents and adults immunized with Toxanal . In the household contact study, the protective efficacy of INFANRIX, in infants, against WHO-defined pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was calculated to be 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%) (for details see INFANRIX prescribing information).

14.2 Immunological Evaluation in Adolescents

In a multicenter, randomized, controlled study conducted in the United States, the immune responses to each of the antigens contained in Toxanal were evaluated in sera obtained approximately 1 month after administration of a single dose of vaccine to adolescent subjects (10 to 18 years of age). Of the subjects enrolled in this study, approximately 76% were 10 to 14 years of age and 24% were 15 to 18 years of age. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either DTwP or a combination of DTwP and DTaP in childhood. The racial/ethnic demographics were as follows: white 85.8%, black 5.7%, Hispanic 5.6%, Oriental 0.8%, and other 2.1%.

Response to Toxanal and Diphtheria Toxoids

The antibody responses to the Toxanal and diphtheria toxoids of Toxanal compared with Td vaccine are shown in Table 6. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) and booster response rates were comparable between Toxanal and the comparator Td vaccine.


N


% ≥0.1 IU/mLa

(95% CI)


% ≥1.0 IU/mLa

(95% CI)


% Booster Responseb

(95% CI)


Anti-tetanus


Toxanal


2,469-2,516


Pre-vaccination


97.7 (97.1, 98.3)


36.8 (34.9, 38.7)




Post-vaccination


100 (99.8, 100)c


99.5 (99.1, 99.7)d


89.7 (88.4, 90.8)c


Td


817-834


Pre-vaccination


96.8 (95.4, 97.9)


39.9 (36.5, 43.4)




Post-vaccination


100 (99.6, 100)


99.8 (99.1, 100)


92.5 (90.5, 94.2)


Anti-diphtheria


Toxanal


2,463-2,515


Pre-vaccination


85.8 (84.3, 87.1)


17.1 (15.6, 18.6)




Post-vaccination


99.9 (99.7, 100)c


97.3 (96.6, 97.9)d


90.6 (89.4, 91.7)c


Td


814-834


Pre-vaccination


84.8 (82.1, 87.2)


19.5 (16.9, 22.4)




Post-vaccination


99.9 (99.3, 100)


99.3 (98.4, 99.7)


95.9 (94.4, 97.2)


Response to Pertussis Antigens

The booster response rates of adolescents to the pertussis antigens are shown in Table 7. For each of the pertussis antigens the lower limit of the two-sided 95% CI for the percentage of subjects with a booster response exceeded the pre-defined lower limit of 80% for demonstration of an acceptable booster response.


N


Toxanal

% Booster Responsea (95% CI)


Anti-PT


2,677


84.5 (83.0, 85.9)


Anti-FHA


2,744


95.1 (94.2, 95.9)


Anti-pertactin


2,752


95.4 (94.5, 96.1)


The GMCs to each of the pertussis antigens 1 month following a single dose of Toxanal in the U.S. adolescent study (N = 2,941 to 2,979) were compared with the GMCs observed in infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age (N = 631 to 2,884). Table 8 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen; the majority of subjects in the study of INFANRIX had anti-PT serology data only). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated . Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations observed in adolescents 1 month after a single dose of Toxanal were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.


GMC Ratio: BOOSTRIX/INFANRIX

(95% CI)


Anti-PT


1.90 (1.82, 1.99)a


Anti-FHA


7.35 (6.85, 7.89)a


Anti-pertactin


4.19 (3.73, 4.71)a

14.3 Immunological Evaluation in Adults

A multicenter, randomized, observer-blinded study, conducted in the United States, evaluated the immunogenicity of Toxanal compared with the licensed comparator Tdap vaccine (Sanofi Pasteur SA). Vaccines were administered as a single dose to subjects (N = 2,284) who had not received a tetanus-diphtheria booster within 5 years. The immune responses to each of the antigens contained in Toxanal were evaluated in sera obtained approximately 1 month after administration. Approximately 33% of patients were 19 to 29 years of age, 33% were 30 to 49 years of age and 34% were 50 to 64 years of age. Among subjects in the combined vaccine groups, 62% were female; 84% of subjects were white, 8% black, 1% Asian, and 7% were of other racial/ethnic groups.

Response to Toxanal and Diphtheria Toxoids

The antibody responses to the Toxanal and diphtheria toxoids of Toxanal compared with the comparator Tdap vaccine are shown in Table 9. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between Toxanal and the comparator Tdap vaccine.


N


% ≥0.1 IU/mLa

(95% CI)


% ≥1.0 IU/mLa

(95% CI)


Anti-tetanus


Toxanal


1,445-1,447


Pre-vaccination


95.9 (94.8, 96.9)


71.9 (69.5, 74.2)


Post-vaccination


99.6 (99.1, 99.8)b


98.3 (97.5, 98.9)b


Tdap


727-728


Pre-vaccination


97.2 (95.8, 98.3)


74.7 (71.4, 77.8)


Post-vaccination


100 (95.5, 100)


99.3 (98.4, 99.8)


Anti-diphtheria


Toxanal


1,440-1,444


Pre-vaccination


85.2 (83.3, 87.0)


23.7 (21.5, 26.0)


Post-vaccination


98.2 (97.4, 98.8)b


87.9 (86.1, 89.5)c


Tdap


720-727


Pre-vaccination


89.2 (86.7, 91.3)


26.5 (23.3, 29.9)


Post-vaccination


98.6 (97.5, 99.3)


92.0 (89.8, 93.9)


Response to Pertussis Antigens

Booster response rates to the pertussis antigens are shown in Table 10. For the FHA and pertactin antigens, the lower limit of the 95% CI for the booster responses exceeded the pre-defined limit of 80% demonstrating an acceptable booster response following Toxanal. The PT antigen booster response lower limit of the 95% CI (74.9%) did not exceed the pre-defined limit of 80%.


N


Toxanal

% Booster Responsea

(95% CI)


Anti-PT


1,419


77.2 (74.9, 79.3)b


Anti-FHA


1,433


96.9 (95.8, 97.7)c


Anti-pertactin


1,441


93.2 (91.8, 94.4)c


The GMCs to each of the pertussis antigens 1 month following a single dose of Toxanal in the U.S. adult (19 to 64 years of age) study were compared with the GMCs observed in infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age. Table 11 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated . Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations observed in adults 1 month after a single dose of Toxanal were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.


GMC Ratio: BOOSTRIX/INFANRIX

(95% CI)


Anti-PT


1.39 (1.32, 1.47)a


Anti-FHA


7.46 (6.86, 8.12)a


Anti-pertactin


3.56 (3.10, 4.08)a

14.4 Immunological Evaluation in the Elderly

The U.S. elderly (65 years of age and older) study, a randomized, observer-blinded study, evaluated the immunogenicity of Toxanal (N = 887) compared with a U.S.-licensed comparator Td vaccine (N = 445) (Sanofi Pasteur SA). Vaccines were administered as a single dose to subjects who had not received a tetanus-diphtheria booster within 5 years. Among all vaccine recipients, the mean age was approximately 72 years of age; 54% were female and 95% were white. The immune responses to each of the antigens contained in Toxanal were evaluated in sera obtained approximately 1 month after administration.

Response to Toxanal and Diphtheria Toxoids and Pertussis Antigens

Immune responses to Toxanal and diphtheria toxoids and pertussis antigens were measured 1 month after administration of a single dose of Toxanal or a comparator Td vaccine. Anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL) were comparable between Toxanal and the comparator Td vaccine (Table 12).


Toxanal

(N = 844-864)


Td

(N = 430-439)


Anti-tetanus


% ≥0.1 IU/mL (95% CI)


96.8 (95.4, 97.8)a


97.5 (95.6, 98.7)


% ≥1.0 IU/mL (95% CI)


88.8 (86.5, 90.8)a


90.0 (86.8, 92.6)


Anti-diphtheria


% ≥0.1 IU/mL (95% CI)


84.9 (82.3, 87.2)a


86.6 (83.0, 89.6)


% ≥1.0 IU/mL (95% CI)


52.0 (48.6, 55.4)b


51.2 (46.3, 56.0)


The GMCs to each of the pertussis antigens 1 month following a single dose of Toxanal were compared with the GMCs of infants following a 3-dose primary series of INFANRIX administered at 3, 4, and 5 months of age. Table 13 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated . Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations in the elderly (65 years of age and older) 1 month after a single dose of Toxanal were non-inferior to those of infants following a primary vaccination series with INFANRIX.


GMC Ratio: BOOSTRIX/INFANRIX

(95% CI)


Anti-PT


1.07 (1.00, 1.15)a


Anti-FHA


8.24 (7.45, 9.12)a


Anti-pertactin


0.93 (0.79, 1.10)a

14.5 Concomitant Vaccine Administration

Concomitant Administration with Meningococcal Conjugate Vaccine

The concomitant use of Toxanal and a tetravalent meningococcal (groups A, C, Y, and W-135) conjugate vaccine (Sanofi Pasteur SA) was evaluated in a randomized study in healthy adolescents 11 to 18 years of age. A total of 1,341 adolescents were vaccinated with Toxanal. Of these, 446 subjects received Toxanal administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects received Toxanal followed by meningococcal conjugate vaccine 1 month later, and 449 subjects received meningococcal conjugate vaccine followed by Toxanal 1 month later.

Immune responses to diphtheria and Toxanal toxoids (% of subjects with anti-tetanus and anti-diphtheria antibodies ≥1.0 IU/mL by ELISA), pertussis antigens (booster responses and GMCs), and meningococcal antigens (vaccine responses) were measured 1 month (range: 30 to 48 days) after concomitant or separate administration of Toxanal and meningococcal conjugate vaccine. For Toxanal given concomitantly with meningococcal conjugate vaccine compared with Toxanal administered first, non-inferiority was demonstrated for all antigens, with the exception of the anti-pertactin GMC. The lower limit of the 95% CI for the GMC ratio was 0.54 for anti-pertactin (pre-specified limit ≥0.67). For the anti-pertactin booster response, non-inferiority was demonstrated. It is not known if the efficacy of Toxanal is affected by the reduced response to pertactin.

There was no evidence that Toxanal interfered with the antibody responses to the meningococcal antigens when measured by serum bactericidal assays (rSBA) when given concomitantly or sequentially (meningococcal conjugate vaccine followed by Toxanal or Toxanal followed by meningococcal conjugate vaccine).

Concomitant Administration with FLUARIX (Influenza Virus Vaccine)

The concomitant use of Toxanal and FLUARIX was evaluated in a multicenter, open-label, randomized, controlled study of 1,497 adults 19 to 64 years of age. In one group, subjects received Toxanal and FLUARIX concurrently (n = 748). The other group received FLUARIX at the first visit, then 1 month later received Toxanal (n = 749). Sera was obtained prior to and 1 month following concomitant or separate administration of Toxanal and/or FLUARIX, as well as 1 month after the separate administration of FLUARIX.

Immune responses following concurrent administration of Toxanal and FLUARIX were non-inferior to separate administration for diphtheria (seroprotection defined as ≥0.1 IU/mL), Toxanal (seroprotection defined as ≥0.1 IU/mL and based on concentrations ≥1.0 IU/mL), pertussis toxin (PT) antigen (anti-PT GMC) and influenza antigens (percent of subjects with hemagglutination-inhibition [HI] antibody titer ≥1:40 and ≥4-fold rise in HI titer). Non-inferiority criteria were not met for the anti-pertussis antigens FHA and pertactin. The lower limit of the 95% CI of the GMC ratio was 0.64 for anti-FHA and 0.60 for anti-pertactin and the pre-specified limit was ≥0.67. It is not known if the efficacy of Toxanal is affected by the reduced response to FHA and pertactin.

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Toxanal is available in 0.5-mL single-dose vials and disposable prefilled TIP-LOK syringes (packaged without needles):

NDC 58160-842-01 Vial in Package of 10: NDC 58160-842-11

NDC 58160-842-05 Syringe in Package of 1: NDC 58160-842-34

NDC 58160-842-43 Syringe in Package of 10: NDC 58160-842-52

Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen.

17 PATIENT COUNSELING INFORMATION

The patient, parent, or guardian should be:


Toxanal, FLUARIX, INFANRIX, and TIP-LOK are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.

Manufactured by GlaxoSmithKline Biologicals

Rixensart, Belgium, U.S. License 1617, and

GSK Vaccines GmbH

Marburg, Germany, U.S. License 1617

Distributed by GlaxoSmithKline

Research Triangle Park, NC 27709

©2016 the GSK group of companies. All rights reserved.

BTX:29PI

Toxanal pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Toxanal available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Toxanal destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Toxanal Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Toxanal pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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Frequently asked Questions

Can i drive or operate heavy machine after consuming Toxanal?

Depending on the reaction of the Toxanal after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Toxanal not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Toxanal addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Toxanal, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Toxanal consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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