ProZinc (Canada)

Company: Boehringer Ingelheim Animal Health

CATS

Sterile

Protamine Zinc Recombinant Human Insulin Injectable Suspension

40 IU/mL

Veterinary Use Only

DIN 02405202

Description

ProZinc^® is a cloudy white injectable suspension. Each mL of ProZinc^® contains:

Active Ingredient

40 IU recombinant human insulin, USP;

Preservative: Phenol 2.50 mg;

Non-Medicinal Ingredients: Protamine sulfate, zinc oxide, glycerin, dibasic sodium phosphate heptahydrate, hydrochloric acid, sodium hydroxide and water for injection.

ProZinc Indications

ProZinc^® is indicated for the reduction of hyperglycemia and hyperglycemia-associated clinical signs in cats with diabetes mellitus.

Dosage and Administration

USE OF A SYRINGE OTHER THAN A U-40 SYRINGE WILL RESULT IN INCORRECT DOSING.

FOR SUBCUTANEOUS INJECTION ONLY.

ProZinc^® insulin should be mixed by gently rolling the vial prior to withdrawing each dose from the vial. Using a U-40 insulin syringe, the injection should be administered subcutaneously twice daily on the back of the neck or on the side of the cat.

Always provide the Cat Owner Information Sheet with each prescription.

The initial recommended ProZinc^® dose is 0.2 - 0.7 IU insulin/kg body weight every 12 hours. The dose should be given concurrently with or right after a meal. The veterinarian should re-evaluate the cat at appropriate intervals and adjust the dose based on both clinical signs and glucose nadirs until adequate glycemic control has been attained.

In the effectiveness field study, glycemic control was considered adequate if the glucose nadir from a 9-hour blood glucose curve was between 4.44 and 8.33 mmol/L (80 - 150 mg/dL) and clinical signs of hyperglycemia such as polyuria, polydipsia and weight loss were improved.

Further adjustments in the dosage may be necessary if there are changes in the cat’s diet, body weight, or concomitant medication, or if the cat develops concurrent infection, inflammation, neoplasia or an additional endocrine or other medical disorder.

In cats, clinical diabetic remission may be possible. It is important to monitor for signs of hypoglycemia and make dosage adjustments accordingly.

Contraindications

ProZinc^® insulin is contraindicated in cats sensitive to protamine zinc recombinant human insulin or any other ingredients in the ProZinc^® product.

ProZinc^® insulin is contraindicated during episodes of hypoglycemia.

Cautions:

FOR SUBCUTANEOUS INJECTION IN CATS ONLY.

The safety and effectiveness of ProZinc^® insulin in kittens or breeding, pregnant or lactating cats has not been evaluated.

Owners should be advised to observe for signs of hypoglycemia (see Cat Owner Information Sheet). Use of this product, even at established doses, has been associated with hypoglycemia. An animal with signs of hypoglycemia should be treated immediately. Glucose should be given orally or intravenously as dictated by clinical signs. Insulin should be temporarily withheld and, if indicated, the dosage adjusted.

Any change in insulin should be made cautiously and only under a veterinarian’s supervision. Changes in insulin strength, manufacturer, type, species (human, animal) or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage.

Appropriate diagnostic tests should be performed to rule out other endocrinopathies in diabetic cats that are difficult to regulate.

Animals presenting with severe ketoacidosis, anorexia, lethargy, and/or vomiting should be stabilized with short-acting insulin and appropriate supportive therapy until their condition is stabilized. As with all insulin products, careful patient monitoring for hypoglycemia and hyperglycemia are essential to attain and maintain adequate glycemic control and to prevent associated complications.

Progestogens, certain endocrinopathies and glucocorticoids can have an antagonistic effect on insulin activity. Progestogen and glucocorticoid use should be avoided.

Warnings

Keep out of reach of children.

Avoid contact with eyes. In case of contact, immediately flush eyes with running water for at least 15 minutes.

Accidental injection may cause hypoglycemia. In case of accidental injection, seek medical attention immediately.

Exposure to product may induce a local or systemic allergic reaction in sensitized individuals.

Adverse Reactions

ProZinc^® insulin, like other insulin products, is not free from adverse reactions.

Owners should be advised of the potential for adverse reactions and be informed of the associated clinical signs (See Cat Owner Information Sheet).

Potential adverse reactions include: hypoglycemia, insulin antagonism/resistance, rapid insulin metabolism, insulin-induced hyperglycemia (Somogyi Effect) and local or systemic reactions.

Hypoglycemia can occur at the prescribed dose or following an overdose (see Overdose section below). In mild cases, offer the animal its usual food. Signs may include: weakness, depression, behavioral changes, muscle twitching and anxiety. More serious symptoms can be treated with immediate administration of a glucose solution. Without prompt treatment, severe cases of hypoglycemia can progress to seizures, coma and death.

Appropriate veterinary monitoring of blood glucose, adjustment of insulin dose and regimen as needed and stabilization of diet and activity help minimize the risk of hypoglycemic episodes. The attending veterinarian should evaluate adverse reactions on a case-by-case basis to determine if an adjustment in therapy is appropriate or if alternative therapy should be considered.

Local injection site reactions were very rarely reported and resolved without cessation of therapy.

Overdose:

An overdose of insulin can result in hypoglycemia. If a cat is given an overdose of insulin (or an overdose is suspected), it should be examined by a veterinarian immediately.

Efficacy Study Information:

45 Day Effectiveness Field Study:

A total of 187 client-owned cats were enrolled in a 45-day field study, with 176 receiving ProZinc^® insulin. One hundred and fifty-one (151) cats were included in the effectiveness analysis. The patients included various purebred and mixed breed cats ranging in age from 3 to 19 years and in weight from 2.1 to 9.4 kg. Of the cats included in the effectiveness analysis, 101 were castrated males, 49 were spayed females, and 1 was an intact female.

Cats were started on ProZinc^® insulin at a dose of 0.2 - 0.7 IU/kg twice daily. Cats were evaluated at 7, 14, 30, and 45 days after initiation of therapy and the dose was adjusted based on clinical signs and results of the glucose nadir from 9-hour blood glucose curves on Days 7, 14, and 30.

Effectiveness was based on successful control of diabetes which was defined as improvements in at least one blood glucose variable (glucose curve mean, nadir or fructosamine) and at least one clinical sign (polyuria, polydipsia or body weight). Of the 151 cats, 115 (76.2%) were considered successful. Blood glucose curve means decreased from 23.07 mmol/L (415.3 mg/dL) on Day 0 to 11.29 mmol/L (203.2 mg/dL) by Day 45 and the mean blood glucose nadir decreased from 22.66 mmol/L (407.9 mg/dL) on Day 0 to 7.91 mmol/L (142.4 mg/dL) on Day 45. Mean fructosamine values decreased from 505.9 μmol/L on Day 0 to 380.7 μmol/L on Day 45.

136 Day Extended Use Field Study

Cats that completed the effectiveness study were eligible to enroll in an extended use field study. In this study 145 cats received ProZinc^® insulin for up to an additional 136 days. The mean fructosamine value was 342.0 μmol/L after a total of 181 days of ProZinc^® therapy.

Storage

Store upright at 2-8°C. Do not freeze. Protect from light.

Presentation:

10 mL multi-dose vials.

Boehringer Ingelheim Animal Health Canada Inc., 5180 South Service Road, Burlington ON L7L 5H4

Revised: 03-2019

DOGS

Sterile

Protamine Zinc Recombinant Human Insulin Injectable Suspension

40 IU/mL

Veterinary Use Only

DIN 02405202

Description

ProZinc^® is a cloudy white injectable suspension. Each mL of ProZinc^® contains:

Active Ingredient

40 IU recombinant human insulin, USP;

Preservative: Phenol 2.50 mg;

Non-Medicinal Ingredients: Protamine sulfate, zinc oxide, glycerin, dibasic sodium phosphate heptahydrate, hydrochloric acid, sodium hydroxide and water for injection.

ProZinc Indications

ProZinc^® is indicated for the reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs with diabetes mellitus.

Dosage and Administration

USE OF A SYRINGE OTHER THAN A U-40 SYRINGE WILL RESULT IN INCORRECT DOSING.

FOR SUBCUTANEOUS INJECTION ONLY.

DO NOT SHAKE OR AGITATE THE VIAL. ProZinc^® insulin should be mixed by gently rolling the vial prior to withdrawing each dose from the vial. Once mixed, ProZinc^® suspension has a white, cloudy appearance. Clumps or visible white particles can form in insulin suspensions: do not use the product if clumps or visible white particles persist after gently rolling the vial.

Using a U-40 insulin syringe, the injection should be administered subcutaneously on the back of the neck or on the side of the dog.

Always provide the Dog Owner Information Sheet with each new vial.

Starting dose: The recommended starting dose for ProZinc^® is 0.5-1.0 IU insulin/kg of body weight (0.2-0.5 IU insulin/ pound) once daily.

The dose selected should be based on the dog’s medical history and previous use of insulin. For naïve dogs, the recommended dose is the lower end of this range.

For dogs with poorly controlled diabetes mellitus transitioning from another insulin, the dose may be slightly higher within the starting range. When transitioning from another insulin, ProZinc® should be started once daily, regardless of the frequency of prior insulin use.

All dogs, when starting insulin should have their blood glucose and general condition closely monitored.

The dose should be given concurrently with or right after a meal. The veterinarian should re-evaluate the dog at appropriate intervals and adjust the dose and frequency based on both clinical signs and laboratory test results (the blood glucose curve values and shape, nadir, and fructosamine) until adequate glycemic control has been attained. In the effectiveness field study, glycemic control was considered adequate if the glucose nadir from a 9-hour blood glucose curve was between 4.5-7 mmol/L (80-125 mg/dL), the maximum blood glucose was ≤16.7 mmol/L (300 mg/dL), and clinical signs of hyperglycemia such as polyuria, polydipsia, or weight loss were improved.

Changing to twice daily dosing: Twice daily dosing should be considered if the duration of insulin action is determined to be inadequate with once daily dosing. Use caution when adjusting from once daily to twice daily dosing because ProZinc^® may have prolonged duration of action in some dogs (see Clinical Pharmacology). The veterinarian should closely monitor the duration of action using blood glucose curves to avoid the increased risk of hypoglycemia. If twice daily dosing is initiated, the two doses should each be approximately 25% less than the once daily dose required to attain an acceptable glucose nadir. For example, if a dog receiving 10 units of ProZinc^® once daily has an acceptable nadir but inadequate duration of activity, the dose should be changed to 7 units twice daily (round down to the nearest whole unit).

Further adjustments in the dosage may be necessary with changes in the dog’s diet, body weight, or concomitant medication, or if the dog develops concurrent infection, inflammation, neoplasia, or an additional endocrine or other medical disorders.

Contraindications

ProZinc^® insulin is contraindicated in dogs sensitive to protamine zinc recombinant human insulin or any other ingredients in the ProZinc^® product.

ProZinc^® insulin is contraindicated during episodes of hypoglycemia.

Cautions:

Dogs presenting with severe ketoacidosis, anorexia, lethargy, and/or vomiting should be stabilized with short-acting insulin and appropriate supportive therapy until their condition is stabilized. As with all insulin products, careful patient monitoring for hypoglycemia and hyperglycemia is essential to attain and maintain adequate glycemic control and to prevent associated complications. Overdose can result in profound hypoglycemia and death.

Glucocorticoids, progestogens, and certain endocrinopathies can have an antagonistic effect on insulin activity. Glucocorticoid and progestogen use should be avoided.

The safety and effectiveness of ProZinc^® in breeding, pregnant, and lactating dogs has not been evaluated.

The safety and effectiveness of ProZinc^® in puppies has not been evaluated.

Owners should be advised to observe for signs of hypoglycemia (see Dog Owner Information Sheet). Use of this product, even at established doses, has been associated with hypoglycemia. An animal with signs of hypoglycemia should be treated immediately. Glucose should be given orally or intravenously as dictated by clinical signs. Insulin should be temporarily withheld and, if indicated, the dosage adjusted.

Any change in insulin should be made cautiously and only under a veterinarian’s supervision. Changes in insulin strength, manufacturer, type, species (human, animal) or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage.

Appropriate diagnostic tests should be performed to rule out other endocrinopathies in diabetic dogs that are difficult to regulate.

Warnings

Keep out of reach of children. Avoid contact with eyes. In case of contact, immediately flush eyes with running water for at least 15 minutes. Accidental injection may cause hypoglycemia. In case of accidental injection, seek medical attention immediately. Exposure to product may induce a local or systemic allergic reaction in sensitized individuals.

Adverse Reactions

In a 182-day field study, 276 diabetic dogs received ProZinc^®. The most common adverse reactions were lethargy, anorexia, hypoglycemia, vomiting, seizures, shaking, diarrhea, and ataxia.

The adverse events listed here reflect reporting and not necessarily causality.

Table 1 summarizes the adverse reactions reported in the study. Clinical signs of hypoglycemia varied and included seizure, collapse, ataxia, staggering, trembling, twitching, shaking, disorientation, lethargy, weakness, and vocalization. In Table 1, the individual clinical signs that were observed during the episodes of hypoglycemia are captured as separate adverse reactions and a single dog may have experienced more than one clinical sign of hypoglycemia.

Table 1. Adverse events seen in the safety population (276 dogs)

Injection site reactions: Seven dogs (2.5%) had injection site reactions and all injection site reactions resolved without cessation of ProZinc^® therapy.

Diabetic ketoacidosis and pancreatitis: Eleven dogs were diagnosed with diabetic ketoacidosis. Four of these 11 dogs died or were euthanized, one after one dose of ProZinc^®.

Twenty-one dogs were diagnosed with pancreatitis. Seven of these 21 dogs died or were euthanized due to complications of pancreatitis. Four dogs had concurrent diabetic ketoacidosis and pancreatitis, three of which died or were euthanized. Not all the deaths were considered related to ProZinc^®.

Deaths: Thirty-six (36) dogs died or were euthanized, six of which were possibly related to ProZinc^®. One dog died from recurrent episodes of pancreatitis, and one died after developing severe vomiting and diarrhea followed by a seizure. Four dogs were euthanized: one developed severe pancreatitis and azotemia, one had recurrent episodes of pancreatitis and diabetic ketoacidosis, and two for lack of effectiveness.

INFORMATION FOR OWNERS

Please refer to the Client Information Sheet for Dogs for more information about ProZinc^®. ProZinc^®, like other insulin products, is not free from adverse reactions. Owners should be advised of the potential for adverse reactions and be informed of the associated clinical signs. Potential adverse reactions include hypoglycemia, insulin antagonism/resistance, rapid insulin metabolism, insulin-induced hyperglycemia (Somogyi Effect), and local or systemic reactions. The most common adverse reaction observed is hypoglycemia. Signs may include weakness, depression, behavioral changes, muscle twitching, and anxiety. In severe cases of hypoglycemia, seizures and coma can occur.

Hypoglycemia can be fatal if an affected dog does not receive prompt treatment. Appropriate veterinary monitoring of blood glucose, adjustment of insulin dose and regimen as needed, and stabilization of diet and activity help minimize the risk of hypoglycemic episodes. The attending veterinarian should evaluate other adverse reactions on a case-by-case basis to determine if an adjustment in therapy is appropriate, or if alternative therapy should be considered.

Overdose:

An overdose of insulin can result in hypoglycemia and death. If an overdose is suspected, treatment to restore euglycemia should be initiated immediately by the dog owner or veterinarian and the dog should be examined by a veterinarian immediately.

Pharmacology

ProZinc^® was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design at doses of 0.5 IU/kg (5 dogs), 0.8 IU/kg at a single site (10 dogs), or 0.8 IU/kg at three separate sites (6 dogs). Insulin and glucose concentrations were measured over 24 hours. The shapes of insulin and glucose curves were variable among dogs; and the relationship between insulin dose, concentration, and glucose-lowering effect was nonlinear (Table 2).

Table 2. Pharmacodynamics of three dosing groups

Efficacy Study Information:

A total of 276 client-owned dogs were enrolled in an 84-day field study followed by a 98-day extended-use phase with 276 dogs receiving ProZinc^®. The dogs included various purebred and mixed breed dogs ranging in age from 2 to 16 years and in weight from 3.3 to 123 pounds. There were 128 neutered males, 8 intact males, 134 spayed females and 6 intact females. Two hundred twenty-four dogs (224) were included in the effectiveness analysis.

Dogs were started on ProZinc^® at a dose of 0.5-1.0 IU/kg (0.2-0.5 IU/lb) once daily. Dogs were evaluated at 7, 14, 21, 28, 42, 63 and 84 days after initiation of therapy. The dose was adjusted based on clinical signs and results of 9-hour blood glucose curves on Days 7, 14, 21, 28, 42, 63 and 84.

Table 3 below summarizes the mean dose (IU/kg/day) for Day 0 and 84 for once and twice a day dosing.

Table 3. Mean dose (IU/kg) for Day 0 and Day 84

Efficacy was based on successful control of diabetes, which was defined as improvement in at least one laboratory variable (blood glucose curve mean, blood glucose curve nadir, or fructosamine) and at least one clinical sign (polyuria, polydipsia, or weight loss). Based on this definition, 162 of 224 cases (72%) were considered successful.

There were 97/138 (70.2%) successful once daily animals and 67/90 (74.4%) successful twice daily animals.

Storage

Store upright at 2-8°C. Do not freeze. Protect from light.

Presentation:

10 mL multi-dose vials.

Boehringer Ingelheim Animal Health Canada Inc., 5180 South Service Road, Burlington ON L7L 5H4

Revised: 03-2019

PROZINC^® is a registered trademark of Boehringer Ingelheim Animal Health USA Inc. Used under license.

86942844

449954-01

CPN: 1182192.0