INSECTS EXTRACTS

Israel - English - Ministry of Health

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Active ingredient:
INSECTS EXTRACTS
Available from:
TRUPHARM MARKETING 1985 LTD.
ATC code:
V01AA07
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
INSECTS EXTRACTS
Administration route:
INTRADERMAL
Prescription type:
Required
Manufactured by:
ABELLO ALK S.A., USA
Therapeutic group:
INSECTS
Therapeutic area:
INSECTS
Therapeutic indications:
Skin testing and immunotherapy.
Authorization number:
138 52 25160 00
Authorization date:
2012-11-30

DESCRIPTION

Center-Al®(Allergenic extracts,Alum Precipitated) is prepared from

aqueous allergenic extracts by the formation of an aluminum hydroxide

precipitated complex. It is supplied as a sterile suspension in multiple

dose vials for subcutaneous injection. 0.4% Phenol is added as a

preservative.

This product is compounded and diluted on a PNU basis. Extracts

containing Short Ragweed Pollen also bear a labeled potency

declaration in terms ofAntigen E content.

CLINICALPHARMACOLOGY

Numerous studies have confirmedAntigen E (AgE) as the major

antigenassociated with Short Ragweed pollinosis. In a well controlled

study, purifiedAntigen E was significantly superior to placebo in

amelioration of symptoms associated with Short Ragweed pollinosis. 1

Therefore, it is essential that the physician be aware ofAgE content of

allergenic extracts administered for hyposensitization therapy.

Some studies have indicated that for most patients a cumulativeAntigen

E dosage of less than 0.1 unit is not immunizing (sufficient to stimulate

specific IgG antibodies). 2 This, however, does not suggest that a 0.1 unit

is a maximum tolerated dose. Most moderately sensitive patients may

tolerate a dosage ten to fifty times greater. For exquisitely sensitive

patients who cannot tolerate an immunizing dose of this preparation, the

physician should consider immunotherapy with alternatives to

conventional aqueous allergenic extract.

Alum precipitated bacterial and viral vaccines and alum precipitated

toxoids have been effectively and routinely used in immunization

injections for many years.The explanation usually given for the effect of

such preparations is that the physical chemical absorption of an antigen

onto an alum complex results in a slower release of the antigen with a

consequent prolongation of the antigenic stimulus.

The treatment consists of the subcutaneous injection of gradually

increasing doses of the allergens to which the patient is allergic. It has

been demonstrated that this method of treatment induces an increased

tolerance to the allergens responsible for the symptoms on subsequent

exposure.Although the exact relationships between allergen, skin-

sensitizing antibody (IgE) and the blocking antibody (IgG) have notbeen

precisely established, clinically confirmed immunological studies have

demonstrated the safety of Center-Alextracts and effectiveness in

terms of symptom reduction and IgG response consistent with dose

administered. 3

In a controlled study with Center-AlRagweed given pre-seasonally,

patients were selected and matched by histamine release toAntigen E

and assigned to treatment groups:Aqueous, Center-Al, and Placebo 3 .

All patients were highly sensitive to RagweedAntigen E, reacting to

<0.001 mcgAntigen E/mLas determined by intradermal skin testing.

These patients received a pre-seasonal course of immunotherapy and

achieved a mean cumulative dose of 52 units ofAntigen E (27,365

PNU) in 13 to 19 injections. Starting doses in these patients were 10

PNU or approximately 0.02 units ofAgE.This dosage was found to be

significantly superior to Placebo as measured by symptom scores

during the ragweed pollen season.

Although maximum tolerated doses for Center-Alexpressed inAgE

content have not specifically been studied, one investigator reported

maximum tolerated doses with Center-Alragweed at 2,000-5,000 PNU

(4-10 units ofAntigen E) with previously untreated patients. 9 At least

three investigators using mixed (tall and short) ragweed extracts

demonstrated a maximum tolerated peak dose of 2,000 to 10,000 PNU

in 10-13 injections in moderately sensitive patients. 6,10-12 This was

achieved by roughly doubling the dose in each successive injection at

low dosages (<1,000 PNU) and if well tolerated, increasing the dosage

approximately 50% until maximum tolerated dose for each patient was

achieved.

Reaction rates for these patients were significantly lower than patients

treated with aqueous extracts with the same or more conservative

INDICATIONS ANDUSAGE

Hyposensitization (injection) therapy is a treatment for patients

exhibiting allergic reactions to seasonal pollens, dust mites, molds,

animal danders, and various other inhalants, in situations where the

offending allergen cannot be avoided.

Prior to the initiation of therapy, clinical sensitivity should be established

by careful evaluation of the patient’s history confirmed by diagnostic

skin testing. Hyposensitization should not be prescribed for sensitivities

to allergens which can be easily avoided.

CONTRAINDICATIONS

Apatient should not be immunized against a substance which the

patient has not demonstrated symptoms and/or tissue-fixed IgE

antibodies as demonstrated by skin testing. Immunotherapy should not

be attempted in patients with active asthma, severe respiratory

obstruction, or cardiovascular disease.

There is some evidence, although inconclusive, that routine

immunizations may exacerbate autoimmune diseases.

Hyposensitization should be given cautiously to patients with this

predisposition.The physician must weigh risk to benefit in these rare

cases.

Patients withAlzheimer’s disease, Down’s syndrome and renal

insufficiency are theoretically at risk from aluminum intake, including

alum precipitated allergenic extracts.

WARNINGS

Patients should always be observed for at least 20-30 minutes after any

injection. In the event of a marked systemic reaction, application of a

tourniquet above the injection site and administration of 0.2 mLto

1.0mLof Epinephrine injection (1:1,000) are recommended. Maximal

recommended dose for children under 2 years of age is 0.3 mL.

Maximal recommended dose for children between 2 and 12 years of

age is 0.5 mL.The tourniquet is then gradually released. Patients under

treatment with beta-blockers may be refractory to the usual dose of

epinephrine.

PRECAUTIONS

Information For Patients:Patients should be instructed to describe

any active allergic symptoms such as rhinitis, wheezing, dyspnea, etc.

prior to injection including any late reactions from previous

administration. Patients should be instructed to remain in the office for

20 to 30 minutes after injection to monitor for adverse reactions.Also,

see ADVERSE REACTIONSandWARNINGSsections.

General:

Center-AlAllergenic Extracts,Alum Precipitated, are not to be

used for intradermal testing.

Store at temperatures 2°and 8°C at all times, even during use.

DO NOTFREEZE. Freezing may cause agglomeration.

Shake vial thoroughly to disperse suspension prior to removal of

the dose to be administered.

Aseparate sterile syringe and needle should be used for each

individual patient, to prevent transmission of homologous serum

hepatitis and other infectious agents from one person to another.

Injections are to be administered subcutaneously with the usual

sterile precautions, preferably in the upper outer aspects of the

arm, using a sterile tuberculin-type syringe and 25 or 26 gauge

needle,¹⁄₂to¹⁄₄in length.

Avoid injecting intravenously. Pull back gently on syringe plunger

and note if blood enters the syringe. If blood should enter the

syringe, withdraw the needle and reinsert at another site,

Allergenic extracts slowly become less potent with age. During

the course of treatment, it may be necessary to continue therapy

with a vial of extract bearing a later expiration date.The initial

dose of the extract bearing the later expiration date should be

lowered to a safe non-reaction-eliciting level, usually reducing the

dosage of the first injection of the new vial 50-75% of the

previous well tolerated dose of the older vial.

Subcutaneous nodules may develop at injection sites.The

incidence of nodules increases with higher dosage of individual

products and with extemporaneous mixtures at lower dosage. No

single dose should provide more than 5,000 PNU whether as

single allergen or mixture nor should it exceed 0.5 mLin volume.

If nodules occur, the highest single dose administered should be

limited to a maximum of 0.2 mL(2,000 PNU).

DRUG INTERACTIONS:

Center-AlAllergenic Extracts,Alum Precipitated, are not to be mixed

with any non-alum containing allergen(s) or with other types of alum

precipitated products. Such mixing may free the alum-absorbed

allergens.

Center-AlAllergenic Extracts,Alum Precipitated, should be diluted only

with Sterile Diluent forAllergenic Extracts (Phenol-Saline) containing

0.9% Sodium Chloride, 0.4% Phenol. Use of other types of diluents may

result in re-solution of some of the alum-complexed allergen thereby

resulting in release of free aqueous extracts.

Patients receiving beta-blockers may not be responsive to epinephrine

or an inhaled bronchodilator.

PREGNANCY- CATEGORYC:Animal reproduction studies have not

been conducted with Center-Al(Allergenic Extracts,Alum

Precipitated).It is also not known whether Center-Alcan cause fetal

harm when administered to a pregnant woman or can affect

reproduction capacity.

Controlled studies of hyposensitization with moderate to high doses of

allergenic extracts during conception and all trimesters of pregnancy

have failed to demonstrate any risk to the fetus or to the mother.

However, on the basis of histamine’s known ability to contract the

uterine muscle, the release of significant amounts of histamine from

allergen exposure or hyposensitization overdose should be avoided on

theoretical grounds.Therefore, allergenic extracts should be used

cautiously in a pregnant woman and only if clearly needed.

PEDIATRIC USE:Children can receive the same dose as adults,

however, to minimize discomfort associated with dose volume it may be

advisable to reduce the volume of the dose by one-half and administer

the injection at two different sites.

NURSING MOTHERS:It is not known if allergens administered

subcutaneously appear in human milk. Because many drugs are

excreted in human milk, caution should be exercised when allergenic

extracts are administered to a nursing woman.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:

Studies in animals have not been performed.

ADVERSE REACTIONS

Local:Reactions at the site of injection may be immediate or delayed.

Immediate wheal and erythema reactions are ordinarily of little

consequence, but if very large may be the first manifestation of a

systemic reaction. If large local reactions occur, the patient should be

observed for systemic symptoms for which treatment is outlined below.

Delayed reactions start several hours after injection with local edema,

erythema, itching or pain.They are usually at their peak at 24 hours and

usually require no treatment.Antihistamine drugs may be administered

orally.

The next therapeutic dose should be reduced to the dose which did not

elicit a reaction, and subsequent doses increased more slowly, i.e., use

Systemic:It should be noted that anaphylaxis and deaths following the

injection of mite and other extracts, including pollen extracts, have been

reported byThe British Committee on Safety in Medicine. 13 Fatalities

from immunotherapy in the United States since 1945 have been

extensively reviewed by Lockey, R.F., et al. 14 and also more recently by

Reid, M.J., et al. 15 With careful attention to dosage and administration,

such reactions occur infrequently, but it must be remembered that

allergenic extracts are highly potent to sensitive individuals and

OVERDOSE could result in anaphylactic symptoms.Therefore, it is

imperative that physicians administering allergenic extracts understand

and be prepared for the treatment of severe reactions.

Systemic reactions are characterized by one or more of the following

symptoms: sneezing, mild to severe generalized urticaria, itching other

than at the injection site, extensive or generalized edema, wheezing,

asthma, dyspnea, cyanosis, tachycardia, lacrimation, marked

perspiration, cough, hypotension, syncope and upper airway

obstruction. Symptoms may progress to shock and death. Patients

should always be observed for at least 20-30 minutes after any injection.

Volume expanders and vasopressor agents may be required to reverse

hypotension. Inhalational bronchodilator and parenteral aminophylline

may be required to reverse bronchospasm. Severe airway obstruction,

unresponsive to bronchodilator, may require tracheal intubation.

In the event of a marked systemic reaction, application of a tourniquet

above the injection site and administration of 0.2 mLto 1.0 mLof

Epinephrine Injection (1:1,000) are recommended. Maximal

recommended dose for children under 2 years of age is 0.3 mL.

Maximal recommended dose for children between 2 and 12 years of

age is 0.5 mL.The tourniquet is then gradually released.

The next therapeutic injection of extract should be reduced to the dose

which did not elicit a reaction, and subsequent doses increased more

slowly, i.e., use of intermediate dilutions.

Adverse Events should be reported via MedWatch (1-800-FDA-1088),

Adverse Experience Reporting, HFM-210 Center for Biologics

Evaluation & Research, Food & DrugAdministration, 1401 Rockville

Pike, Rockville, MD 20852-1448.

DOSAGEANDADMINISTRATION

The starting dose for immunotherapy is related directly to a patient’s

sensitivity as determined by carefully executed percutaneous

(prick/puncture) and intracutaneous (intradermal) skin testing with non-

alum adsorbed allergenic extract.Ageneral rule is to begin at 1/10 of

the intradermal dose that produces sum of erythema of 50 mm

(approximately a 2+ positive skin test reaction). Patient’s response to

skin testing is graded on the basis of the size of the erythema and

wheal. Refer to the diagnostic allergenic extract package enclosure for

specific information.

TRANSFER OF PATIENTS FROM OTHERAQUEOUS

EXTRACTSTO CENTER-ALEXTRACTS

Patients may be transferred from other aqueous allergens to Center-Al

Alum Precipitated Extracts during treatment.To avoid untoward

reactions, it may be necessary to initiate treatment as though the patient

were previously untreated. In transferring from standardized extracts,

the more rapid rate of decline in activity of aqueous extract relative to

alum precipitated extract must be considered in cautiously transferring

patients to alum precipitated extract.

Caution should be observed since the Center-Alpreparation may be

more potent than the aqueous product.

TRANSFER OF PATIENTS FROM OTHERALUM-COMPLEXED

EXTRACTS TO CENTER-ALEXTRACTS

Patients may be transferred from other alum-complexed allergenic

extracts to Center-AlAlum Precipitated extracts. In order to avoid

untoward reactions, it is recommended that previous therapy be

disregarded and therapy with Center-Albe initiated as though the

patient were previously untreated.The first dose of Center-Alshould be

related to the patient’s sensitivity, determined by history and confirmed

by skin testing. CAUTION: Center-AlAlum Precipitated extracts should

not be mixed with other alum precipitated or aqueous extracts.

PRE-SEASONALAND PERENNIALMETHOD OF TREATMENT

The use of Center-AlAllergenic extract,Alum Precipitated, in the

treatment of patients by the pre-seasonal method should be started 10

to 12 weeks prior to the usual onset of symptoms.Therapy should be

initiated early enough to permit a graduated series of doses at weekly

intervals. It is recommended that the larger doses be spaced 2 to 3

weeks apart and that the top dose be reached prior to the season.

Increased tolerance acquired through hyposensitization can vary from a

few to several months.To assure prolongation of this acquired

tolerance, perennial or year-round treatment is recommended.

Some physicians continue therapy into or through the season by

repeating a reduced MAINTENANCE dose at 4 to 6 week intervals.

SUGGESTED DOSAGE SCHEDULE

Atreatment schedule is related directly to the patient's degree of

sensitivity, determined initially by clinical history and skin testing, and

continuously by response to therapeutic doses.Thus, an individual

treatment schedule for each patient must be established during the

course of therapy. Maximum protection can be obtained with a dosage

kept constantly below the patient’s limit of tolerance. Every precaution

should be taken to avoid a systemic or generalized reaction which in

addition to being dangerous, may depress rather than increase the

patient’s tolerance.

FORALLPREPARATIONS (EXCEPT SHORT RAGWEEDAND

MIXED SHORTAND TALLRAGWEED)

LabeledAntigen E content of extracts containing Short Ragweed at a

weight/volume concentration more dilute than 1:10 may have been

obtained by calculation from theAntigen E assay value of a more

concentrated extract that was analyzed, officially released by the Office

of Biologics, and subsequently diluted.

Below is listed a suggested dosage schedule for Pre-Seasonal

Treatment.Acolumn has been left blank forAgE dosage of short

ragweed containing extracts.

Note:For extracts of short ragweed or equal part mixture of Short and

Tall Ragweed refer toAgE dosage schedule.TheAgE content for those

products is indicated on the vial label.The physician may use the

formula below to determine theAgE dosage for each injection.

AgE dosage can be monitored by using the formula:

LabeledAgE X dose in PNU = dose inAgE

Labeled PNU/mL

Note:Suggested dosage schedules which follow have not been

subjected to adequate and well controlled trials to establish their safety

and efficacy.

Dose Vial Volume PNU AgE

No. Strength Injected Per Dose Dose

100 PNU/mL 0.1 mL 10

100 PNU/mL 0.2 mL 20

100 PNU/mL 0.5 mL 50

1,000 PNU/mL 0.1 mL 100

1,000 PNU/mL 0.25 mL 250

1,000 PNU/mL 0.5 mL 500

10,000 PNU/mL 0.1 mL 1,000

10,000 PNU/mL 0.2 mL 2,000

10,000 PNU/mL 0.3 mL 3,000

10,000 PNU/mL 0.4 mL 4,000

MAINTENANCE DOSE:

10,000 PNU/mL 0.5 mL 5,000

NO SINGLE DOSE SHOULD EXCEED 5,000 PNU. For continuing

therapy with extracts containing Short Ragweed, see following section

on DosageAdjustments.

SHORTRAGWEED EQUALPARTS MIXES OF SHORTANDTALL

RAGWEED (DOSAGE BASED ONANTIGEN CONTENT)

Suggested dosage schedule for Short Ragweed and Equal Part Mixture

of Short andTall Ragweed:

Dose AgE Volume AgE

No Units/mL Injected Per Dose

0.04

0.08

0.25 1.0

MAINTENANCE DOSE:

0.25 20

NO SINGLE DOSE SHOULD EXCEED 20 UNITS

DOSAGE ADJUSTMENTS

(FOR PRODUCTS CONTAINING SHORTRAGWEED)

AgE is important in adjusting dosage of Short Ragweed extracts to

accurately transfer a patient from older extracts to fresher material. In

such cases, the dosage ofAgE should be considered in addition to the

protein nitrogen units.Antigen E concentration continuously declines in

Short Ragweed Pollen extracts at a rate that varies with the formulation

of the product.Aqueous extracts retainAntigenEpotencyless

effectively than 50% glycinerated orAlum Precipitated extracts.Antigen

E is most stable in freeze-dried extracts.These differences are reflected

in the expiration date declared on the vial label.The continuous decline

should be considered.Also, where Ragweed is a component of an

allergen mixture, clinical response to the other components must be

considered in adjustment of dosage based onAgE content alone.

CAUTION:Asmall percent of individuals allergic to Short Ragweed are

more sensitive to minor antigens such as Ra3 and Ra5 thanAgE.There

is no correlation between the amount of these antigens and eitherAgE

or PNU content.

HOW SUPPLIED

Therapeutic Center-AlAllergenic Extracts,Alum Precipitated, are

supplied in 10 mLand 30 mLvials, in concentrations of 10,000 PNU/mL

and 20,000 PNU/mL. Prescription treatment sets for individual patients

are also available. Center-Almust be stored continuously at 2 ºto 8ºC.

DO NOTFREEZE. Diluent: Sterile Diluent for allergenic extracts

(Phenol-Saline) is provided in vials of 4.5 mL, 9.0 mL, and 30 mL.

STORAGE:To maintain stability of allergenic extracts, proper storage

conditions are essential. Bulk concentrates and diluted extracts are to

be stored at 2°to 8°C even during use. Bulk or diluted extracts are not

REFERENCES

Norman, P.S. et. al.: Immunotherapy of hayfever with ragweed

antigen E. Comparisons with whole pollen extract and placebo.

J. Allergy 42:93, 1968.

Van Metre,T.E. et. al.:Acontrolled study of the effectiveness of

the Rinkel method of immunotherapy for ragweed pollen

hayfever. J.Allergy Clin. Immunol. 61:384, 1978.

Norman, P.S. and Lichtenstein, L.M.: Comparisons of alum

precipitated and unprecipitated aqueous ragweed pollen

extracts in the treatment of hayfever. J.Allergy Clin. Immunol.

61:384, 1978.

Ransom, J.H.: Clinical and laboratory evaluation of alum

precipitated ragweed extract.Ann.Allergy 28:22, 1970.

Ransom, J.H.: Frequency of reactions to alum precipitated

ragweedextract. Ann. Allergy 29:635, 1971.

Lazar, H. and Leoffler, J.A.: Evaluation of an alum precipitated

mixed ragweed antigen: a three-year study.Ann.Allergy 28:214,

1970.

Norman, P.S., Winkenwerder, W.L., and Lichtenstein, L.M.:Trials

of alum precipitated pollen extracts in the treatment of hayfever.

J.Allergy Clin. Immunol. 50:31, 1972.

Nelson, H.S.: Long-term immunotherapy with aqueous and alum

precipitated grass extracts.Ann.Allergy 45:333, 1980.

Norman,. P.S.:The role of In-Vitro assays in the evaluation of

immunotherapy. RecentAdvances in Immunotherapy. Port

Washington, NY1973.

Lazar, H.: Clinical presentation covering 6 years of observation.

RecentAdvances in Immunotherapy. Port Washington, NY

1973.

Haynes, J.T.:Aclinical study of 23 ragweed sensitive patients.

RecentAdvances in Immunotherapy. Port Washington, NY

1973.

Ransom, J.H.: Ragweed patient study. RecentAdvances in

Immunotherapy. Port Washington, NY1973.

Committee on the Safety of Medicines. CSM update:

desensitizing vaccines.Brit. Med. J. 1986; 293:948.

Lockey, R.F.et al.:Fatalities from immunotherapy (IT) and skin

testing (ST).J.Allergy Clin. Immunol. 1987; 79:660.

Reid, M.J.et al.:Survey of fatalities from skin testing and

immunotherapy. 1985-1989.J.Allergy Clin. Immunol. 1993;92:6.

Distributed in Canada by:

WesternAllergy Services, LTD.

121-6154 Westminister Highway

Richmond, B.C. V7C 4O4

Revision: June 2002

DIRECTIONS FOR USE OF CENTER -AL®THERAPEUTIC

ALLERGENIC EXTRACTSALUM PRECIPITATED

POLLENS, HOUSE DUSTS, MOLDS,

INHALANTSANDEPIDERMALS

DOSAGE BASED ON

PROTEIN NITROGEN CONTENT

Port Washington, NY11050

WARNING

This allergenic extract is intended for use by physicians who are

experienced in the administration of allergenic extracts for

immunotherapy and the emergency care of anaphylaxis, or for use

under the guidance of an allergy specialist.These allergenic

extracts are not directly interchangeable with allergenic extracts of

the same labeled potency from different manufacturers.The patient

must be re-evaluated with the newly selected extract. Patients being

switched from other types of extracts such as aqueous extracts,

glycerinated extract, or alum precipitated extracts from other

suppliers to this allergenic extract should be started as though they

were coming under treatment for the first time. Patients should be

instructed to recognize adverse reaction symptoms and cautioned

to contact the physician’s office if reaction symptoms occur. Aswith

all allergenic extracts, severe systemic reactions may occur. In

certain individuals, these life-threatening reactions may be

fatal.Patients should be observed for 20 to 30 minutes following

treatment, and emergency measures, as well as personnel trained

in their use, should be immediately available in the event of a life-

threatening reaction.

Sensitive patients may experience severe anaphylactic reactions

resulting in respiratory obstruction, shock, coma and/or death.

Patients with unstable asthma or steroid dependent asthmatics

andpatients with underlying cardiovascular disease are at greater

risk to a fatal outcome from a systemic allergic reaction. If treated,

these high risk patients should be started at lower (more

conservative) doses and be progressed more slowly to a

maintenance dose. Usually this is a lower dose than for those

patients without these predispositions. (See DOSAGE AND

ADMINISTRATION)

This product should not be injected intravenously. Deep

subcutaneous routes have proven to be safe. See the warnings,

precautions, adverse reactions and overdosage sections below.

Patients receiving beta-blockers may not be responsive to

epinephrine or inhaled bronchodilators. Respiratory obstruction not

responding to parenteral or inhaled bronchodilators may require

theophylline, oxygen, intubation and the use of life support systems.

Parenteral fluid and/or plasma expanders may be utilized for

treatment of shock.Adrenocorticosteroids may be administered

parenterally or intravenously. Refer to the warnings, precautions

and adverse reaction sections below.

DESCRIPTION

Center-Al® (Allergenic extracts, Alum Precipitated) is prepared from

aqueous allergenic extracts by the formation of an aluminum hydroxide

precipitated complex. It is supplied as a sterile suspension in multiple

dose vials for subcutaneous injection. 0.4% Phenol is added as a

preservative.

This product is compounded and diluted on a PNU basis. Extracts

containing

Short

Ragweed

Pollen

also

bear

labeled

potency

declaration in terms of Antigen E content.

CLINICAL PHARMACOLOGY

Numerous studies have confirmed Antigen E (AgE) as the major

antigen associated with Short Ragweed pollinosis. In a well controlled

study,

purified Antigen

significantly

superior

placebo

amelioration of symptoms associated with Short Ragweed pollinosis.

Therefore, it is essential that the physician be aware of AgE content of

allergenic extracts administered for hyposensitization therapy.

Some studies have indicated that for most patients a cumulative Antigen

E dosage of less than 0.1 unit is not immunizing (sufficient to stimulate

specific IgG antibodies).

This, however, does not suggest that a 0.1 unit

is a maximum tolerated dose. Most moderately sensitive patients may

tolerate a dosage ten to fifty times greater. For exquisitely sensitive

patients who cannot tolerate an immunizing dose of this preparation, the

physician

should

consider

immunotherapy

with

alternatives

conventional aqueous allergenic extract.

Alum precipitated bacterial and viral vaccines and alum precipitated

toxoids

have

been

effectively

routinely

used

immunization

injections for many years. The explanation usually given for the effect of

such preparations is that the physical chemical absorption of an antigen

onto an alum complex results in a slower release of the antigen with a

consequent prolongation of the antigenic stimulus.

The treatment consists of the subcutaneous injection of gradually

increasing doses of the allergens to which the patient is allergic. It has

been demonstrated that this method of treatment induces an increased

tolerance to the allergens responsible for the symptoms on subsequent

exposure. Although the exact relationships between allergen, skin-

sensitizing antibody (IgE) and the blocking antibody (IgG) have not been

precisely established, clinically confirmed immunological studies have

demonstrated the safety of Center-Al extracts and effectiveness in

terms of symptom reduction and IgG response consistent with dose

administered.

In a controlled study with Center-Al Ragweed given pre-seasonally,

patients were selected and matched by histamine release to Antigen E

and assigned to treatment groups: Aqueous, Center-Al, and Placebo

All patients were highly sensitive to Ragweed Antigen E, reacting to

<0.001 mcg Antigen E/mL as determined by intradermal skin testing.

These patients received a pre-seasonal course of immunotherapy and

achieved a mean cumulative dose of 52 units of Antigen E (27,365

PNU) in 13 to 19 injections. Starting doses in these patients were 10

PNU or approximately 0.02 units of AgE. This dosage was found to be

significantly superior to Placebo as measured by symptom scores

during the ragweed pollen season.

Although maximum tolerated doses for Center-Al expressed in AgE

content have not specifically been studied, one investigator reported

maximum tolerated doses with Center-Al ragweed at 2,000-5,000 PNU

(4-10 units of Antigen E) with previously untreated patients.

At least

three

investigators

using

mixed

(tall

short)

ragweed

extracts

demonstrated a maximum tolerated peak dose of 2,000 to 10,000 PNU

in 10-13 injections in moderately sensitive patients.

6,10-12

This was

achieved by roughly doubling the dose in each successive injection at

low dosages (<1,000 PNU) and if well tolerated, increasing the dosage

approximately 50% until maximum tolerated dose for each patient was

achieved.

Reaction rates for these patients were significantly lower than patients

treated with aqueous extracts with the same or more conservative

dosage regimen.

3,7,8,11

INDICATIONS AND USAGE

Hyposensitization

(injection)

therapy

treatment

patients

exhibiting allergic reactions to seasonal pollens, dust mites, molds,

animal danders, and various other inhalants, in situations where the

offending allergen cannot be avoided.

Prior to the initiation of therapy, clinical sensitivity should be established

by careful evaluation of the patient’s history confirmed by diagnostic

skin testing. Hyposensitization should not be prescribed for sensitivities

to allergens which can be easily avoided.

CONTRAINDICATIONS

A patient should not be immunized against a substance which the

patient

demonstrated

symptoms

and/or

tissue-fixed

antibodies as demonstrated by skin testing. Immunotherapy should not

attempted

patients

with

active

asthma,

severe

respiratory

obstruction, or cardiovascular disease.

There

some

evidence,

although

inconclusive,

that

routine

immunizations

exacerbate

autoimmune

diseases.

Hyposensitization should be given cautiously to patients with this

predisposition. The physician must weigh risk to benefit in these rare

cases.

Patients

with Alzheimer’s

disease,

Down’s

syndrome

renal

insufficiency are theoretically at risk from aluminum intake, including

alum precipitated allergenic extracts.

WARNINGS

Patients should always be observed for at least 20-30 minutes after any

injection. In the event of a marked systemic reaction, application of a

tourniquet above the injection site and administration of 0.2 mL to

1.0 mL of Epinephrine injection (1:1,000) are recommended. Maximal

recommended dose for children under 2 years of age is 0.3 mL.

Maximal recommended dose for children between 2 and 12 years of

age is 0.5 mL. The tourniquet is then gradually released. Patients under

treatment with beta-blockers may be refractory to the usual dose of

epinephrine.

PRECAUTIONS

Information For Patients: Patients should be instructed to describe

any active allergic symptoms such as rhinitis, wheezing, dyspnea, etc.

prior

injection

including

late

reactions

from

previous

administration. Patients should be instructed to remain in the office for

20 to 30 minutes after injection to monitor for adverse reactions. Also,

see ADVERSE REACTIONS and WARNINGS sections.

General:

Center-Al Allergenic Extracts, Alum Precipitated, are not to be

used for intradermal testing.

Store at temperatures 2° and 8°C at all times, even during use.

DO NOT FREEZE. Freezing may cause agglomeration.

Shake vial thoroughly to disperse suspension prior to removal of

the dose to be administered.

A separate sterile syringe and needle should be used for each

individual patient, to prevent transmission of homologous serum

hepatitis and other infectious agents from one person to another.

Injections are to be administered subcutaneously with the usual

sterile precautions, preferably in the upper outer aspects of the

arm, using a sterile tuberculin-type syringe and 25 or 26 gauge

needle,

¹⁄₂

¹⁄₄

in length.

Avoid injecting intravenously. Pull back gently on syringe plunger

and note if blood enters the syringe. If blood should enter the

syringe,

withdraw

needle

reinsert

another

site,

repeating the same precaution.

Allergenic extracts slowly become less potent with age. During

the course of treatment, it may be necessary to continue therapy

with a vial of extract bearing a later expiration date. The initial

dose of the extract bearing the later expiration date should be

lowered to a safe non-reaction-eliciting level, usually reducing the

dosage of the first injection of the new vial 50-75% of the

previous well tolerated dose of the older vial.

Subcutaneous

nodules

develop

injection

sites.

incidence of nodules increases with higher dosage of individual

products and with extemporaneous mixtures at lower dosage. No

single dose should provide more than 5,000 PNU whether as

single allergen or mixture nor should it exceed 0.5 mL in volume.

If nodules occur, the highest single dose administered should be

limited to a maximum of 0.2 mL (2,000 PNU).

DRUG INTERACTIONS:

Center-Al Allergenic Extracts, Alum Precipitated, are not to be mixed

with any non-alum containing allergen(s) or with other types of alum

precipitated

products.

Such

mixing

free

alum-absorbed

allergens.

Center-Al Allergenic Extracts, Alum Precipitated, should be diluted only

with Sterile Diluent for Allergenic Extracts (Phenol-Saline) containing

0.9% Sodium Chloride, 0.4% Phenol. Use of other types of diluents may

result in re-solution of some of the alum-complexed allergen thereby

resulting in release of free aqueous extracts.

Patients receiving beta-blockers may not be responsive to epinephrine

or an inhaled bronchodilator.

PREGNANCY - CATEGORY C: Animal reproduction studies have not

been

conducted

with

Center-Al

(Allergenic

Extracts,

Alum

Precipitated). It is also not known whether Center-Al can cause fetal

harm

when

administered

pregnant

woman

affect

reproduction capacity.

Controlled studies of hyposensitization with moderate to high doses of

allergenic extracts during conception and all trimesters of pregnancy

have failed to demonstrate any risk to the fetus or to the mother.

However, on the basis of histamine’s known ability to contract the

uterine muscle, the release of significant amounts of histamine from

allergen exposure or hyposensitization overdose should be avoided on

theoretical grounds. Therefore, allergenic extracts should be used

cautiously in a pregnant woman and only if clearly needed.

PEDIATRIC USE: Children can receive the same dose as adults,

however, to minimize discomfort associated with dose volume it may be

advisable to reduce the volume of the dose by one-half and administer

the injection at two different sites.

NURSING

MOTHERS:

known

allergens

administered

subcutaneously

appear

human

milk.

Because

many

drugs

excreted in human milk, caution should be exercised when allergenic

extracts are administered to a nursing woman.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:

Studies in animals have not been performed.

ADVERSE REACTIONS

Local: Reactions at the site of injection may be immediate or delayed.

Immediate

wheal

erythema

reactions

ordinarily

little

consequence, but if very large may be the first manifestation of a

systemic reaction. If large local reactions occur, the patient should be

observed for systemic symptoms for which treatment is outlined below.

Delayed reactions start several hours after injection with local edema,

erythema, itching or pain. They are usually at their peak at 24 hours and

usually require no treatment. Antihistamine drugs may be administered

orally.

The next therapeutic dose should be reduced to the dose which did not

elicit a reaction, and subsequent doses increased more slowly, i.e., use

of intermediate dilutions.

Systemic: It should be noted that anaphylaxis and deaths following the

injection of mite and other extracts, including pollen extracts, have been

reported by The British Committee on Safety in Medicine.

Fatalities

from

immunotherapy

United

States

since

1945

have

been

extensively reviewed by Lockey, R.F., et al.

and also more recently by

Reid, M.J., et al.

With careful attention to dosage and administration,

such reactions occur infrequently, but it must be remembered that

allergenic

extracts

highly

potent

sensitive

individuals

OVERDOSE could result in anaphylactic symptoms. Therefore, it is

imperative that physicians administering allergenic extracts understand

and be prepared for the treatment of severe reactions.

Systemic reactions are characterized by one or more of the following

symptoms: sneezing, mild to severe generalized urticaria, itching other

than at the injection site, extensive or generalized edema, wheezing,

asthma,

dyspnea,

cyanosis,

tachycardia,

lacrimation,

marked

perspiration,

cough,

hypotension,

syncope

upper

airway

obstruction. Symptoms may progress to shock and death. Patients

should always be observed for at least 20-30 minutes after any injection.

Volume expanders and vasopressor agents may be required to reverse

hypotension. Inhalational bronchodilator and parenteral aminophylline

may be required to reverse bronchospasm. Severe airway obstruction,

unresponsive to bronchodilator, may require tracheal intubation.

In the event of a marked systemic reaction, application of a tourniquet

above the injection site and administration of 0.2 mL to 1.0 mL of

Epinephrine

Injection

(1:1,000)

recommended.

Maximal

recommended dose for children under 2 years of age is 0.3 mL.

Maximal recommended dose for children between 2 and 12 years of

age is 0.5 mL. The tourniquet is then gradually released.

The next therapeutic injection of extract should be reduced to the dose

which did not elicit a reaction, and subsequent doses increased more

slowly, i.e., use of intermediate dilutions.

Adverse Events should be reported via MedWatch (1-800-FDA-1088),

Adverse

Experience

Reporting,

HFM-210

Center

Biologics

Evaluation & Research, Food & Drug Administration, 1401 Rockville

Pike, Rockville, MD 20852-1448.

DOSAGE AND ADMINISTRATION

The starting dose for immunotherapy is related directly to a patient’s

sensitivity

determined

carefully

executed

percutaneous

(prick/puncture) and intracutaneous (intradermal) skin testing with non-

alum adsorbed allergenic extract. A general rule is to begin at 1/10 of

intradermal

dose

that

produces

erythema

(approximately a 2+ positive skin test reaction). Patient’s response to

skin testing is graded on the basis of the size of the erythema and

wheal. Refer to the diagnostic allergenic extract package enclosure for

specific information.

TRANSFER OF PATIENTS FROM OTHER AQUEOUS

EXTRACTS TO CENTER-AL EXTRACTS

Patients may be transferred from other aqueous allergens to Center-Al

Alum

Precipitated

Extracts

during

treatment.

avoid

untoward

reactions, it may be necessary to initiate treatment as though the patient

were previously untreated. In transferring from standardized extracts,

the more rapid rate of decline in activity of aqueous extract relative to

alum precipitated extract must be considered in cautiously transferring

patients to alum precipitated extract.

Caution should be observed since the Center-Al preparation may be

more potent than the aqueous product.

TRANSFER OF PATIENTS FROM OTHER ALUM-COMPLEXED

EXTRACTS TO CENTER-AL EXTRACTS

Patients may be transferred from other alum-complexed allergenic

extracts to Center-Al Alum Precipitated extracts. In order to avoid

untoward

reactions,

recommended

that

previous

therapy

disregarded and therapy with Center-Al be initiated as though the

patient were previously untreated. The first dose of Center-Al should be

related to the patient’s sensitivity, determined by history and confirmed

by skin testing. CAUTION: Center-Al Alum Precipitated extracts should

not be mixed with other alum precipitated or aqueous extracts.

PRE-SEASONAL AND PERENNIAL METHOD OF TREATMENT

The use of Center-Al Allergenic extract, Alum Precipitated, in the

treatment of patients by the pre-seasonal method should be started 10

to 12 weeks prior to the usual onset of symptoms. Therapy should be

initiated early enough to permit a graduated series of doses at weekly

intervals. It is recommended that the larger doses be spaced 2 to 3

weeks apart and that the top dose be reached prior to the season.

Increased tolerance acquired through hyposensitization can vary from a

several

months.

assure

prolongation

this

acquired

tolerance, perennial or year-round treatment is recommended.

Some physicians continue therapy into or through the season by

repeating a reduced MAINTENANCE dose at 4 to 6 week intervals.

SUGGESTED DOSAGE SCHEDULE

A treatment schedule is related directly to the patient's degree of

sensitivity, determined initially by clinical history and skin testing, and

continuously by response to therapeutic doses. Thus, an individual

treatment schedule for each patient must be established during the

course of therapy. Maximum protection can be obtained with a dosage

kept constantly below the patient’s limit of tolerance. Every precaution

should be taken to avoid a systemic or generalized reaction which in

addition to being dangerous, may depress rather than increase the

patient’s tolerance.

FOR ALL PREPARATIONS (EXCEPT SHORT RAGWEED AND

MIXED SHORT AND TALL RAGWEED)

Labeled Antigen E content of extracts containing Short Ragweed at a

weight/volume concentration more dilute than 1:10 may have been

obtained by calculation from the Antigen E assay value of a more

concentrated extract that was analyzed, officially released by the Office

of Biologics, and subsequently diluted.

Below

listed

suggested

dosage

schedule

Pre-Seasonal

Treatment. A column has been left blank for AgE dosage of short

ragweed containing extracts.

Note: For extracts of short ragweed or equal part mixture of Short and

Tall Ragweed refer to AgE dosage schedule. The AgE content for those

products is indicated on the vial label. The physician may use the

formula below to determine the AgE dosage for each injection.

AgE dosage can be monitored by using the formula:

Labeled AgE

X dose in PNU = dose in AgE

Labeled PNU/mL

Note:

Suggested

dosage

schedules

which

follow

have

been

subjected to adequate and well controlled trials to establish their safety

and efficacy.

Dose

Vial

Volume

PNU

AgE

No.

Strength

Injected

Per Dose

Dose

100 PNU/mL

0.1 mL

100 PNU/mL

0.2 mL

100 PNU/mL

0.5 mL

1,000 PNU/mL

0.1 mL

1,000 PNU/mL

0.25 mL

1,000 PNU/mL

0.5 mL

10,000 PNU/mL

0.1 mL

1,000

10,000 PNU/mL

0.2 mL

2,000

10,000 PNU/mL

0.3 mL

3,000

10,000 PNU/mL

0.4 mL

4,000

10,000 PNU/mL

0.5 mL

5,000

MAINTENANCE DOSE:

10,000 PNU/mL

0.5 mL

5,000

NO SINGLE DOSE SHOULD EXCEED 5,000 PNU. For continuing

therapy with extracts containing Short Ragweed, see following section

on Dosage Adjustments.

SHORT RAGWEED EQUAL PARTS MIXES OF SHORT AND TALL

RAGWEED (DOSAGE BASED ON ANTIGEN CONTENT)

Suggested dosage schedule for Short Ragweed and Equal Part Mixture

of Short and Tall Ragweed:

Dose

AgE

Volume

AgE

No

Units/mL

Injected

Per Dose

0.04

0.08

0.25

MAINTENANCE DOSE:

0.25

NO SINGLE DOSE SHOULD EXCEED 20 UNITS

DOSAGE ADJUSTMENTS

(FOR PRODUCTS CONTAINING SHORT RAGWEED)

AgE is important in adjusting dosage of Short Ragweed extracts to

accurately transfer a patient from older extracts to fresher material. In

such cases, the dosage of AgE should be considered in addition to the

protein nitrogen units. Antigen E concentration continuously declines in

Short Ragweed Pollen extracts at a rate that varies with the formulation

product. Aqueous

extracts

retain

Antigen

potency

less

effectively than 50% glycinerated or Alum Precipitated extracts. Antigen

E is most stable in freeze-dried extracts. These differences are reflected

in the expiration date declared on the vial label. The continuous decline

should be considered. Also, where Ragweed is a component of an

allergen mixture, clinical response to the other components must be

considered in adjustment of dosage based on AgE content alone.

CAUTION: A small percent of individuals allergic to Short Ragweed are

more sensitive to minor antigens such as Ra3 and Ra5 than AgE. There

is no correlation between the amount of these antigens and either AgE

or PNU content.

HOW SUPPLIED

Therapeutic

Center-Al

Allergenic

Extracts,

Alum

Precipitated,

supplied in 10 mL and 30 mL vials, in concentrations of 10,000 PNU/mL

and 20,000 PNU/mL. Prescription treatment sets for individual patients

are also available. Center-Al must be stored continuously at 2º to 8ºC.

NOT FREEZE.

Diluent:

Sterile

Diluent

allergenic

extracts

(Phenol-Saline) is provided in vials of 4.5 mL, 9.0 mL, and 30 mL.

STORAGE: To maintain stability of allergenic extracts, proper storage

conditions are essential. Bulk concentrates and diluted extracts are to

be stored at 2° to 8°C even during use. Bulk or diluted extracts are not

to be frozen. Do not use after the expiration date shown on the vial label.

REFERENCES

Norman, P.S. et. al.: Immunotherapy of hayfever with ragweed

antigen E. Comparisons with whole pollen extract and placebo.

J. Allergy 42:93, 1968.

Van Metre, T.E. et. al.: A controlled study of the effectiveness of

Rinkel

method

immunotherapy

ragweed

pollen

hayfever. J. Allergy Clin. Immunol. 61:384, 1978.

Norman, P.S. and Lichtenstein, L.M.: Comparisons of alum

precipitated

unprecipitated

aqueous

ragweed

pollen

extracts in the treatment of hayfever. J. Allergy Clin. Immunol.

61:384, 1978.

Ransom,

J.H.:

Clinical

laboratory

evaluation

alum

precipitated ragweed extract. Ann. Allergy 28:22, 1970.

Ransom, J.H.: Frequency of reactions to alum precipitated

ragweed extract. Ann. Allergy 29:635, 1971.

Lazar, H. and Leoffler, J.A.: Evaluation of an alum precipitated

mixed ragweed antigen: a three-year study. Ann. Allergy 28:214,

1970.

Norman, P.S., Winkenwerder, W.L., and Lichtenstein, L.M.: Trials

of alum precipitated pollen extracts in the treatment of hayfever.

J. Allergy Clin. Immunol. 50:31, 1972.

Nelson, H.S.: Long-term immunotherapy with aqueous and alum

precipitated grass extracts. Ann. Allergy 45:333, 1980.

Norman,. P.S.: The role of In-Vitro assays in the evaluation of

immunotherapy.

Recent

Advances

Immunotherapy.

Port

Washington, NY 1973.

Lazar, H.: Clinical presentation covering 6 years of observation.

Recent Advances

Immunotherapy.

Port

Washington,

1973.

Haynes, J.T.: A clinical study of 23 ragweed sensitive patients.

Recent Advances

Immunotherapy.

Port

Washington,

1973.

Ransom, J.H.: Ragweed patient study. Recent Advances in

Immunotherapy. Port Washington, NY 1973.

Committee

Safety

Medicines.

update:

desensitizing vaccines. Brit. Med. J. 1986; 293:948.

Lockey, R.F. et al.: Fatalities from immunotherapy (IT) and skin

testing (ST). J. Allergy Clin. Immunol. 1987; 79:660.

Reid, M.J. et al.: Survey of fatalities from skin testing and

immunotherapy. 1985-1989. J. Allergy Clin. Immunol. 1993; 92:6.

Distributed in Canada by:

Western Allergy Services, LTD.

121-6154 Westminister Highway

Richmond, B.C. V7C 4O4

Revision: June 2002

© Alk-Abelló, Inc. 2002

168F

DIRECTIONS FOR USE OF CENTER - AL® THERAPEUTIC

ALLERGENIC EXTRACTS ALUM PRECIPITATED

POLLENS, HOUSE DUSTS, MOLDS,

INHALANTS AND EPIDERMALS

DOSAGE BASED ON

PROTEIN NITROGEN CONTENT

Port Washington, NY 11050

U.S. Government License No. 1256

WARNING

This allergenic extract is intended for use by physicians who are

experienced

administration

allergenic

extracts

immunotherapy and the emergency care of anaphylaxis, or for use

under

guidance

allergy

specialist.

These

allergenic

extracts are not directly interchangeable with allergenic extracts of

the same labeled potency from different manufacturers. The patient

must be re-evaluated with the newly selected extract. Patients being

switched from other types of extracts such as aqueous extracts,

glycerinated

extract,

alum

precipitated

extracts

from

other

suppliers to this allergenic extract should be started as though they

were coming under treatment for the first time. Patients should be

instructed to recognize adverse reaction symptoms and cautioned

to contact the physician’s office if reaction symptoms occur. As with

all allergenic extracts, severe systemic reactions may occur. In

certain individuals, these life-threatening reactions may be

fatal. Patients should be observed for 20 to 30 minutes following

treatment, and emergency measures, as well as personnel trained

in their use, should be immediately available in the event of a life-

threatening reaction.

Sensitive patients may experience severe anaphylactic reactions

resulting in respiratory obstruction, shock, coma and/or death.

Patients with unstable asthma or steroid dependent asthmatics

and patients with underlying cardiovascular disease are at greater

risk to a fatal outcome from a systemic allergic reaction. If treated,

these

high

risk

patients

should

started

lower

(more

conservative)

doses

progressed

more

slowly

maintenance dose. Usually this is a lower dose than for those

patients

without

these

predispositions.

(See

DOSAGE

AND

ADMINISTRATION)

This

product

should

injected

intravenously.

Deep

subcutaneous routes have proven to be safe. See the warnings,

precautions, adverse reactions and overdosage sections below.

Patients

receiving

beta-blockers

responsive

epinephrine or inhaled bronchodilators. Respiratory obstruction not

responding to parenteral or inhaled bronchodilators may require

theophylline, oxygen, intubation and the use of life support systems.

Parenteral

fluid

and/or

plasma

expanders

utilized

treatment of shock. Adrenocorticosteroids may be administered

parenterally or intravenously. Refer to the warnings, precautions

and adverse reaction sections below.

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