Improvest (Canada)

Company: Zoetis

Gonadotropin Releasing Factor Analogue-Diphtheria Toxoid Conjugate Injection

Veterinary Use Only

Sterile solution

For intact male and female pigs intended for slaughter only

Immunological

DIN 02369532

Description

Each mL of IMPROVEST^® injection contains:

● Active ingredient: Gonadotropin Releasing Factor (GnRF) analogue-diphtheria toxoid conjugate, 0.2 mg.

● Non-medicinal ingredients:

- Aqueous, non mineral oil-based adjuvant: Diethylaminoethyl (DEAE)-Dextran, 150 mg.

- Preservative: Chlorocresol, 1.0 mg.

IMPROVEST injection is a sterile solution containing an incomplete analogue of natural gonadotropin releasing factor (GnRF) conjugated to an immunogenic carrier protein, diphtheria toxoid, in an adjuvanted formulation. Immunization with a two dose regimen of IMPROVEST injection, with a four week interval between the two doses, stimulates the pig’s immune system to produce antibodies which can neutralize its own GnRF. Pigs given an initial dose of IMPROVEST injection are immunologically primed but do not produce sufficient antibodies to have any physiological effect. Following receipt of the second dose, the pig’s immune system responds with a strong antibody response. These antibodies bind to and neutralize circulating GnRF in the bloodstream. Neutralization of GnRF blocks the hypothalamic-pituitary-gonadal endocrine axis, thereby temporarily suppressing testicular function in intact male pigs and ovarian function in intact female pigs, including both sex hormone production and reproductive capability, in these injected animals.

Improvest Indications

IMPROVEST injection is indicated for the temporary suppression of testicular function and reduction of boar taint in intact male pigs intended for slaughter. IMPROVEST injection is also indicated for the temporary suppression of ovarian function and the suppression of estrus in intact female pigs intended for slaughter.

Dosage and Administration

IMPROVEST injection should be administered via subcutaneous injection into the post auricular region of the neck, immediately behind the ear. A safety injector should be used, preferably one which has a dual safety system providing both a needle guard and a mechanism to prevent accidental operation of the trigger.

Each intact male or female pig should receive two 2 mL doses of IMPROVEST injection. The first dose should be administered no earlier than 8 weeks of age. The second dose should be administered at least 4 weeks after the first dose. Immunological suppression of testicular function in male pigs and ovarian function in female pigs is achieved within 3 and 4 weeks after the second dose, respectively, and lasts up to 10 weeks after the second dose.

To avoid potential food quality issues (boar taint), male pigs should be slaughtered no earlier than 3 weeks and no later than 10 weeks after the second dose.

In case of misdosing, the animal should be re-dosed immediately.

Under mixed gender housing conditions, male and female pigs should be injected at the same time.

Note: IMPROVEST injection-treated boars will start to return to full reproductive function at a variable period after this time, as evidenced by increases in male sex hormones, testicle size, and intact male behavior.

Contraindications

Do not use in male and female pigs intended for breeding because of the disruption of reproductive function.

CAUTIONS:

Avoid injecting pigs that are unhealthy, wet or dirty.

Subcutaneous injection in intact male and female pigs can cause a transient local injection site reaction that may result in trim loss at slaughter (See Adverse Reactions).

Safety of IMPROVEST injection has not been demonstrated in male and female pigs less than 8 weeks of age.

Do not use in barrows as the safety of IMPROVEST injection has not been evaluated in those animals.

Warnings

No withdrawal period is required for pigs when treated according to the label.

Not for human use. Keep out of reach of children.

Warning for the person administering IMPROVEST injection

Accidental self injection could affect reproductive physiology of both men and women and adversely affect pregnancy. Pregnant women should not administer this product. Women of childbearing age should exercise extreme caution when administering this product. Special care should be taken to avoid accidental self injection and needle stick injury when administering the product. Use a safety injector, preferably one which has a dual safety system providing both a needle guard and a mechanism to prevent accidental operation of the trigger. In case of eye contact, rinse immediately with copious amounts of water. In case of skin contact, wash immediately with soap and water. The product should be stored safely out of the reach of children. As a reminder, it is the prescribing veterinarian’s responsibility to inform drug administrators of the user safety warnings associated with IMPROVEST injection.

Advice to the user in the event of accidental self injection

In the event of accidental self injection, wash the injury thoroughly with clean running water. Seek prompt medical advice and take the package leaflet with you. Do not administer the product and/or any other products with similar action in the future.

Advice to the Physician

Accidental self injection could affect reproductive physiology of both men and women and adversely affect pregnancy. If self injection with IMPROVEST injection is suspected, reproductive physiology should be monitored by assay of testosterone or estrogen levels (as appropriate). The risk of a physiological effect is greater after a second or subsequent accidental injection than after a first injection. Clinically meaningful suppression of gonadal function should be managed with supportive endocrine replacement therapy until normal function returns. The patient should be advised not to administer IMPROVEST injection and/or any other products with similar action in the future.

The material safety data sheet (MSDS) contains more detailed occupational safety information. To report adverse reactions in users or to obtain a copy of the MSDS for this product, call 1-800-461-0917.

Adverse Reactions

In very rare cases, anaphylactoid type reactions (breathing difficulty, collapse, cyanosis and hypersalivation associated with or without muscle twitching or emesis) have been observed in pigs within a few minutes after the first injection with duration up to 30 minutes. In a small number of animals death occurred following the reaction, however most animals recovered without treatment and did not appear to react to subsequent injections.

The observations made from the field efficacy studies were consistent with the observations made during the target animal safety studies of transient inflammation at the injection site. IMPROVEST injection did not cause an unexpected frequency or severity of injection site reactions.

ANIMAL SAFETY:

Margin Of Safety

The safety of two doses of IMPROVEST injection was evaluated in intact male swine in a U.S. study. Thirty 9-week old intact boars received two subcutaneous doses of IMPROVEST injection in the same location 14 days apart. The boars received one of three treatments: Saline Control (12 mL), IMPROVEST injection at the intended dose (2 mL, 1X), or IMPROVEST injection at 6 times the intended dose (12 mL, 6X). Boars were clinically monitored daily. In addition, observation and measurement of injection sites, body weight, quantitative feed consumption, hematology, and clinical chemistry analyses were also obtained. A complete postmortem examination was conducted on each boar 14 days after the second injection. IMPROVEST injection, administered subcutaneously at the label dose (2 mL) resulted in mild transient injection site reactions at the 1X dose and caused clinical signs of systemic inflammation at 6X the intended dose. The signs of inflammation included depression, stiffness of the neck lasting up to five days, reduction in feed intake, and lower body weights. Multiple swollen joints and associated lameness, which may be signs of systemic inflammation, were observed in one 6X boar. Evaluation of blood work revealed increased white blood cell counts (eosinophilia and neutrophilia); slight increases in total serum protein (above normal reference range in 50% of the 6X boars) and globulin (above the normal reference range in 40% of the 6X boars); and slight decreases in serum albumin in 6X boars. Injection sites for the 6X boars showed clinically detectable firmness persisting in all animals for 14 days after the second injection. Pain and sensitivity at the injection site persisted for up to five days, and erythema and heat were more prominent in the 6X boars than in the 1X boars. Mild to moderate chronic inflammation and discoloration in the subcutaneous tissues at the injection site were observed. In all IMPROVEST injection-treated boars, atrophy of testes, prostate, and bulbourethral glands were observed as expected consequences associated with the intended effect of the drug. At the label 2 mL dose, IMPROVEST injection may cause transient injection site inflammation.

Injection Site Safety

Injection site safety was evaluated following the injection of IMPROVEST injection into healthy 17-week old boars in a U.S. study. The treated boars received two 2 mL doses of IMPROVEST injection into the same injection site location 28 days apart, while the control boars received saline. Daily monitoring included clinical evaluation and observation and measurement of injection sites. Two days after the second injection, postmortem observations of injection sites were conducted. All clinical signs of observable injection site swelling were resolved within 24 hours, and pain on palpation resolved by 48 hours post-injection. Firmness persisted for up to 11 days after the first injection in 10% of boars. Gross injection site alterations consisted of subcutaneous edema with tan or red discoloration. Two 2 mL doses of IMPROVEST injection, administered 28 days apart into the same location resulted in transient injection site reactions following each injection and resulted in discoloration of tissue at the injection site which was observable approximately 48 hours after the second injection.

Injection site safety was also evaluated in several studies conducted in Australia, EU and the U.S. following the administration of IMPROVEST injection in intact male pigs. In one injection site tissue tolerance study using a formulation of IMPROVEST injection with a different preservative, 8-week old pigs were administered IMPROVEST injection; injection site swellings of up to 4x8 cm were commonly observed. A gradual resolution of the local reactions occurred, but in 20-30% of the animals these persisted on palpation for more than 42 days. When administered to older pigs (14-23 weeks of age) injection site swellings ranging from 2 to 5 cm in diameter were commonly observed, and injection site reactions at slaughter were commonly observed when the second injection was given only 4 weeks before slaughter. In an overdose safety study using a formulation of IMPROVEST injection with a different preservative, administration of a double dose (4 mL) of IMPROVEST injection to 8 week old piglets commonly resulted in palpable injection site reactions. The largest reactions were seen 7 days post administration when the maximum size was 13x7 cm. By two weeks post administration the maximum size had decreased to 8x4 cm showing a gradual resolution of the local reactions. The general health of the animals was not affected.

Field Safety

During the conduct of pivotal field efficacy studies, carried out in the U.S., Australia and EU, IMPROVEST injection did not cause unusual clinical signs or an unexpected frequency or severity of injection site reactions. The field safety observations from these studies were consistent with the observations made during the target animal safety studies of transient inflammation at the injection sites. Adverse events, as reported, were not uniquely attributable to IMPROVEST injection.

EFFICACY:

Evidence of temporary suppression of testicular function was provided in a series of studies showing that within 1-2 weeks after the second injection of IMPROVEST injection, anti-GnRF antibody levels increase significantly. With this rise in anti-GnRF antibodies, the levels of gonadal sex hormones were substantially reduced, the size of the testes, and spermatogenesis suppressed, as was the expression of typical male behaviors (aggression and sexual, e.g., mounting). Full suppression of testicular function was demonstrated to last from 3 to 10 weeks after the second dose. IMPROVEST injection-treated boars started to return to full reproductive function at a variable period after this time.

Evidence of temporary suppression of ovarian function was provided in a series of studies showing that within 4 weeks after the second injection of IMPROVEST injection, anti-GnRF antibody levels increase significantly. With this rise in anti-GnRF antibodies, the levels of gonadal sex hormones were substantially reduced, the weight of the ovaries was significantly decreased, and the percentage of gilts with visible follicles was low. Full suppression of ovarian function was demonstrated to last from 4 to 10 weeks after the second dose. Suppression of physical signs of estrus (red, swollen vulva) was observed in gilts slaughtered at an age of at least 22 weeks and at an average live weight of at least 125 kg. Administration of IMPROVEST injection to female pigs resulted in increased back fat thickness compared to non-treated female pigs.

Evidence to assess the acceptability of pork from IMPROVEST injection-treated male pigs was provided through a series of consumer taste panels using consumers deemed sensitive to the taste of “tainted” meat. The presence of boar taint was evaluated on the basis of pork aroma and flavor and not by chemical analysis. Three consumer taste panel studies were conducted in the U.S. to demonstrate the difference of pork obtained from IMPROVEST injection-treated and intact boars. A surgically castrated male group was not evaluated during these studies. In these three studies, 822 sensitive consumers evaluated cooked pork loin samples from IMPROVEST injection-treated and intact boars. These pigs were raised to market weight, treated with IMPROVEST injection as per product labelling and slaughtered 3 to 10 weeks after receipt of the second dose of IMPROVEST injection. The consumers found the aroma and flavor of pork from the IMPROVEST injection-treated pigs to be more acceptable than from the intact boars in all three studies.

Storage

Store between 2 and 8°C. Once broached, product may be stored under refrigeration for 28 days. Store vials in carton until used. Protect from light. Protect from freezing.

PRESENTATION: IMPROVEST injection is available in 100 mL and 250 mL vials.

Zoetis^® and Improvest are registered trademarks of Zoetis or its licensors.

Zoetis Canada Inc., Kirkland QC H9H 4M7

1536-11-4

CPN: 1198451.7