Oxyglobin Solution

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  • Oxyglobin Solution Indications
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Oxyglobin Solution

This treatment applies to the following species:
Manufacturer: OPK Biotech

hemoglobin glutamer - 200 (bovine)

FOR INTRAVENOUS USE IN DOGS ONLY

Oxyglobin Solution Caution

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Description

Oxyglobin® contains 13 g/dL polymerized hemoglobin of bovine origin in a modified Lactated Ringer’s Solution containing Water for Injection USP 100 g/dL, NaCl USP 113 mmol/L, KCl USP 4 mmol/L, CaCl2-2H2O USP 1.4 mmol/L, NaOH NF 10 mmol/L, Sodium Lactate USP 27 mmol/L, N-acetyl-L-cysteine USP 200 mg/dL. It has an osmolality of 300 mOsm/kg. It is a sterile, clear dark purple solution with a pH of 7.8. It is a distribution of hemoglobin polymers with less than 5% of the hemoglobin as unstabilized tetramers, approximately 50% has a molecular weight between 65 and 130 kD, and no more than 10% has a molecular weight >500 kD. It contains ≤ 0.1 µg/mL free-glutaraldehyde and ≤ 0.05 EU/mL endotoxin.

Pharmacology

Oxyglobin® is a hemoglobin-based oxygen carrying fluid which increases plasma and total hemoglobin concentration and thus increases arterial oxygen content. The colloid osmotic pressure, measured at 13 g/dL, is 43 mm Hg. Infusion of Oxyglobin® results in expansion of the plasma volume, an effect that decreases over the succeeding 24 hours. The degree of plasma volume expansion and resulting effect on the hemodynamic state by a given dose are based on the dog’s pre-existing intravascular status. The terminal elimination half-life of the drug is estimated to range between 18 and 43 hours for dosages of 10-30 mL/kg (Table A) in dogs. The increase in half-life with dose suggests a saturable elimination process. Depending on the dose, greater than 95% of the administered dose is expected to be eliminated from the body at 4 to 9 days after infusion. A laboratory study in dogs established that an increase in total hemoglobin by as little as 0.7 g/dL with a hemoglobin-based oxygen carrying fluid restored normal tissue oxygenation.1 Table A provides data from a laboratory study on the post-infusion duration (hours) for which plasma Oxyglobin® levels remained above this therapeutically critical level (1 g/dL).

Table A: Pharmacokinetic Parameters at Multiple Dose Levels after a Single Infusion of Oxyglobin®

Dose
(mL/kg)

Immediate
Post infusion
concentration (g/dL)

Duration (hours):
Oxyglobin®
levels over 1 g/dL

Terminal
half-Life*
(hours)

Cleared from
plasma
(days)***

10

1.5 - 2.0

11 - 23

18 - 26

4 - 5

15

2.0 - 2.5

23 - 29

19 - 30

4 - 6

21

3.4 - 4.3

66 - 70

25 - 34

5 - 7

30

3.6 - 4.8

74 - 82

22 - 43**

5 - 9**

* range based on mean ± SD

**range based on estimated mean value with bounds of a 95% prediction interval

***range based on 5 terminal half-lives

Metabolism and Excretion: In a toxicokinetic study involving 24 healthy young adult male Beagle dogs, transient hemoglobinuria was noted for less than 4 hours after completion of the Oxyglobin® infusion. The duration of hemoglobinuria in diseased dogs has not been determined.

Oxyglobin Solution Indications

Oxyglobin® is indicated for the treatment of anemia in dogs by increasing systemic oxygen content (plasma hemoglobin concentration) and improving the clinical signs associated with anemia, regardless of the cause of anemia (hemolysis, blood loss, or ineffective erythropoiesis) (See EFFECTIVENESS).

Contraindications

Plasma volume expanders, such as Oxyglobin®, are contraindicated in dogs with a pre-disposition to volume overload such as those with advanced cardiac disease (i.e., congestive heart failure) or otherwise severely impaired cardiac function or oliguria or anuria. The safety of Oxyglobin® was not assessed in dogs with these conditions.

Warnings

Overdosage or an excessively rapid administration rate (i.e., > 10 mL/kg/hr) may result in circulatory overload.

OVERDOSAGE: Accidental overdosage or an excessive rate of administration (i.e., >10 mL/kg/hr) could result in immediate cardiopulmonary effects, in which case infusion of Oxyglobin® should be discontinued immediately until signs abate. Signs of circulatory overload such as pulmonary edema, pleural effusion, increased central venous pressure, dyspnea, or coughing may occur. Treatment of circulatory overload may be necessary.

Precautions

The safety and efficacy of repeat administration of Oxyglobin® have not been demonstrated in dogs. The safety of Oxyglobin® for use in breeding dogs and pregnant or lactating bitches has not been determined. Teratogenic effects were observed in preliminary reproductive toxicity studies in rats using a related polymerized bovine hemoglobin product. The safety and efficacy of Oxyglobin® have not been evaluated in dogs with disseminated intravascular coagulopathy, thrombocytopenia with active bleeding, hemoglobinemia and hemoglobinuria, or autoagglutination.

If an immediate hypersensitivity reaction occurs, infusion of Oxyglobin® should be immediately discontinued and appropriate treatment administered. If a delayed type of hypersensitivity reaction occurs, immunosuppressant therapy is recommended.

Concomitant treatment of the cause of anemia should be instituted.

Treatment with Oxyglobin® at a dosage of 30 mL/kg results in a mild decrease in PCV immediately post infusion. Due to the dilutional effects of Oxyglobin® at that dose, PCV and RBC count are not accurate measures of the degree of anemia for 24 hours following administration. Dilutional effects are not seen at a dosage of 15 mL/kg.

The animal should be adequately hydrated (but not overhydrated) prior to administration. Due to the plasma expanding properties of Oxyglobin®, the possibility of circulatory overload should be considered especially when administering adjunctive intravenous fluids, particularly colloidal solutions. If concurrent fluid therapy is administered, it should be temporarily discontinued during infusion of Oxyglobin®. Close monitoring of central venous pressure (CVP) during and immediately following administration of Oxyglobin® is recommended. If CVP measurement is not feasible, the patient should be carefully monitored for signs of circulatory overload. If CVP increases to a clinically unacceptable level and/or if signs of circulatory overload are observed, the infusion of Oxyglobin® should be temporarily discontinued and reinstituted at a slower rate when signs abate and/or CVP decreases. Use of a diuretic may be indicated.

Clinical Pathology:

Chemistry: The presence of Oxyglobin® in serum may result in artifactual increases or decreases in the results of serum chemistry tests, depending on the type of analyzer and reagents used.

Table B: Valid Analytes by Instrumentation

Idexx
VetLab

Hitachi
All Models

Johnson & Johnson
Ektachem/Vitros

Dupont
Dimension

Beckman
CX7/CX3

sodium
potassium
chloride
BUN
CK
creatinine

sodium
potassium
chloride
BUN
CK
glucose
ALT
AST
calcium

sodium
potassium
chloride
BUN
CK
AST
calcium
magnesium
lipase
glucose

sodium
potassium
chloride
BUN
LDH
calcium

sodium
potassium
chloride
BUN
calcium
glucose

Hematology: No interference. Confirm that hemoglobin is measured, not calculated from red blood cell number.

Coagulation: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) can be accurately determined using methods that are mechanical, magnetic, and light scattering. Optical methods are not reliable for coagulation assays in the presence of Oxyglobin®. Fibrin degradation products can be measured using the Thrombo-Wellcotest kit (Murex® Kent, England).

Urinalysis: Sediment examination is accurate. Dipstick measurements (i.e., pH, glucose, ketones, protein) are inaccurate while gross discoloration of the urine is present.

SAFETY: The safety of Oxyglobin® was assessed in 40 healthy Beagle dogs with induced acute, severe normovolemic anemia (total hemoglobin concentration ≈ 5 g/dL). Oxyglobin® was administered at 0, 30, 60, and 90 mL/kg twice at a 72 hour interval (equivalent to 0, 1X, 2X, 3X the maximum recommended dose given twice, respectively). 13% Human Serum Albumin (HSA) in Saline was a control (90 mL/kg twice at 72 hour interval) used to determine the effects of a protein load compared with Oxyglobin®. There was 100% survival in all groups.

The clinical and pathological effects associated with Oxyglobin® were: Transient clinical signs: yellow-orange discoloration of the skin, ear canals, pinnae, mucous membranes (gums), and sclera, red-dark-green discoloration of feces, brown-black discoloration of urine, red spotting of skin and/or lips (less common finding) and decreased appetite and thirst. Vomiting, diarrhea, and decreased skin elasticity occurred within 48 hours of dosing. The frequency and/or intensity of these clinical signs were dose dependent. Clinical pathology: transient, dose dependent red discoloration of plasma, increases in serum enzyme activity with no corresponding microscopic lesions in the liver: 8-fold mean increase in aspartate aminotransferase (AST) activity (peak activity 200 and 677 U/L at 1X and 2X doses given twice, respectively) and 5-fold mean increase in alanine aminotransferase (ALT) activity at 3X dose given twice only (peak activity 372 U/L), increase in serum total protein (peak concentration 9.9 and 14.6 g/dL at 1X and 3X doses given twice, respectively), and hemoglobinuria.

Gross pathology: Dark yellow-orange-brown discoloration (whole body) and dark areas on gall bladder serosa. Histopathology: Hemosiderin in the renal cortex, arteriolitis (limited duration) and activation of tissue macrophages in multiple organs occurred in all Oxyglobin® treated groups. Microscopic hemorrhage in the gall bladder and evidence of hepatic macrophage activation occurred in only the 2X and 3X dose groups given twice. Reversible, slight to mild renal tubular damage with limited distribution was seen in both the Oxyglobin® treated and HSA in Saline treated control dogs. All findings were dose dependent except for renal tubular protein droplets and casts (indicating saturation of tubular protein reabsorption) and a slight proliferative glomerulopathy (limited duration and distribution) seen in all Oxyglobin® treated groups.

Immunohistopathology: Immunofluorescent antibody staining was performed on kidneys of Oxyglobin® treated dogs in which a glomerulopathy was identified (5/24) to detect deposition of immune complexes. Only one dog with a glomerulopathy (graded slight) had a focal non-specific IgG deposit in a single area in the outer cortex of one kidney in an estimated amount of 30%. Deposits of <25% is considered normal in dogs.

Immunology: Low levels of canine immunoglobin-G class antibodies to bovine hemoglobin (anti-BvHb) were produced in 11/12 Oxyglobin® treated dogs. Due to the limited nature of the study, no relationship between anti-BvHb antibody titer and dose of Oxyglobin® administered could be demonstrated. Observed levels of IgG anti-BvHb are not expected to have any toxicological significance in dogs.

Adverse Reactions

The clinical field trial included dogs with anemia (PCV 6-23%) due to hemolysis (immune mediated, naphthalene toxicity), blood loss (gastrointestinal, traumatic, surgical, rodenticide intoxication), and ineffective erythropoiesis (idiopathic, red cell aplasia, ehrlichiosis, chronic renal failure). Adverse reactions were tabulated by frequency in treated dogs (n=52). The following adverse reactions may be related to Oxyglobin® and/or the underlying disease.

Table C: Frequency of Adverse Reactions in Oxyglobin® Treated Dogs

Adverse Reaction

% of Treated Dogs with Adverse Reaction (n=52)

Discoloration

Mucous Membranes°

Sclera (yellow, red, brown)

Urine (orange, red, brown)

Skin (yellow)

69

56

52

12

Cardiovascular

Increased CVP

Ventricular Arrhythmiav

Ecchymoses/ Petechiae

Bradycardia

33

15

8

6

Gastrointestinal

Vomiting

Diarrhea

Anorexia

35

15

8

Respiratory

Tachypnea

Dyspnea

Pulmonary Edema

Harsh Lung Sounds/Crackles

Pleural Effusion

15

14

12

8

6

Miscellaneous

Fever

Death/ Euthanasia

Peripheral Edema

Hemoglobinuria*

Dehydration

17

15

8

6

6

° yellow, red, purple, brown

measured in 17 dogs only

v AV block, tachycardia, ventricular premature contractions

* measured in 3 dogs only

Adverse reactions occurring in 4% of the dogs treated with Oxyglobin® included: coughing, disseminated intravascular coagulopathy, melena, nasal discharge/crusts (red), peritoneal effusion, respiratory arrest, and weight loss (5-7% body weight). Adverse reactions occurring in less than 2% of the dogs treated with Oxyglobin® included: abdominal discomfort on palpation, acidosis, cardiac arrest, cardiovascular volume overload (by echocardiography), collapse, cystitis, dark stool, discolored soft stool (red-brown) and tongue (purple), focal hyperemic areas on gums, forelimb cellulitis/lameness, hematemesis or hemoptysis (unable to differentiate), hypernatremia, hypotension, hypoxemia, lack of neurologic responses, left forebrain signs, nystagmus, pancreatitis, pendulous abdomen, polyuria, pulmonary thromboembolism, ptosis, reddened pinnae with papules/head shaking, reduction in heart rate, thrombocytopenia (worsening), and venous thrombosis.

Effectiveness

Dose Response Study: A controlled laboratory study was conducted in 30 healthy dogs with induced acute, severe normovolemic anemia (total hemoglobin concentration ≈ 3 g/dL). Oxyglobin®, administered once at a dose of 30 mL/kg, resulted in significantly (p≤0.01) increased arterial oxygen content at 60 minutes and 24 hours following dosing compared with control dogs. A positive correlation was established between arterial oxygen content (laboratory measured) and plasma hemoglobin concentration (clinically measured).

Clinical Field Study: A well controlled clinical field trial involving 64 client-owned dogs (2 months to 15 years old) weighing 2.1 to 71.8 kg with moderate-severe anemia (total hemoglobin concentration 1.7-6.9 g/dL and PCV 6-23%) was conducted at six clinical sites. Dogs were either treated with Oxyglobin® (30 mL/kg) or untreated (with an option to receive Oxyglobin® if condition worsened). Relative to pretreatment, plasma hemoglobin concentration significantly increased (p≤0.001) and clinical signs associated with anemia (lethargy/depression, exercise intolerance, and increased heart rate) significantly improved (p≤0.001) in the Oxyglobin® treated group for at least 24 hours. Treatment success, defined as the lack of need for additional oxygen carrying support (i.e., a blood transfusion) for 24 hours, was 95% in the Oxyglobin® treated group compared with 32% in the control group.

The effectiveness of the lower end of the dose range is supported by controlled laboratory studies (See PHARMACOLOGY).

Dosage and Administration

The recommended dosage of Oxyglobin® is a one time dose of 10 - 30 mL/kg body weight administered intravenously at a rate of up to 10 mL/kg/hr (See PRECAUTIONS). The choice of dose within the recommended range will vary with the patient and the clinical situation. Pharmacokinetic data show that there is an increase in the duration of action with increasing dose. (See PHARMACOLOGY).

For recommendations on patient monitoring during and immediately following Oxyglobin® administration and discussion of conditions which may warrant adjustment in the administration rate see Precautions section. If desired, Oxyglobin® may be warmed to 37°C prior to administration.

Remove overwrap prior to use and use within 24 hours. Oxyglobin® should be administered using aseptic technique via a standard intravenous infusion set and catheter through a central or peripheral vein at a rate of up to 10 mL/kg/hr. Do not administer subcutaneously or intraperitoneally. Do not administer with other fluids or drugs via the same infusion set. Do not add medications or other solutions to the bag. Do not combine the contents of more than one bag.

Use of Oxyglobin® does not require cross-matching with recipient blood. A blood transfusion is not contraindicated in dogs which receive Oxyglobin® nor is Oxyglobin® contraindicated in dogs which have previously received a blood transfusion. Oxyglobin® is intended for single dose use. Any unused Oxyglobin® should be discarded properly in accordance with local requirements for handling veterinary medical waste.

STORAGE CONDITIONS: Store at room temperature or refrigerated (2-30°C). DO NOT FREEZE. Oxyglobin® remains stable for up to 36 months; the expiry date is printed on the bag.

How Supplied

Oxyglobin® is available as follows:

NDC 63075-301-01 - 125 mL single dose bags

NDC 63075-301-02 - 60 mL single dose bags

Oxyglobin® Solution, Biopure Corporation, 11 Hurley Street, Cambridge, MA 02141

NOT FOR HUMAN USE

NADA # 141-067, Approved by FDA

Text Revision Date: February 2004

Biopure Part Number 49-0060 Rev 9

Oxyglobin® Solution and its method of preparation are covered by one or more of the following United States Patents: No. 5,084,558; No. 5,618,919; No. 5,691,452 and No. 5,296,465. Oxyglobin is a registered trademark of Biopure Corporation.

1 Bovine Haemoglobin is More Potent than Autologous Red Blood Cells in Restoring Muscular Tissue Oxygenation after Profound Isovolaemic Haemodilution in Dogs. Standl T., et al. Can J Anaesth. 43(7):714-723.

NAC No.: 10530007

OPK BIOTECH LLC
11 HURLEY STREET, CAMBRIDGE, MA, 02141
Customer Service:   866-933-2472
Website:   www.oxyglobin.com
Every effort has been made to ensure the accuracy of the Oxyglobin Solution information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the US product label or package insert.

Copyright © 2014 North American Compendiums. Updated: 2014-04-11

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