Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE CROFAB is indicated for the management of adult and pediatric patients with North American crotalid envenomation. The term crotalid is used to describe the Crotalinae subfamily (formerly known as Crotalidae) of venomous snakes which includes rattlesnakes, copperheads and cottonmouths/water moccasins. CROFAB is a sheep-derived antivenin indicated for the management of adult and pediatric patients with North American crotalid envenomation. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Do not administer CROFAB to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available. Do not administer CROFAB to patients with a known history of hypersensitivity to any of its components, or to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available. (4)
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5% of subjects) were urticaria, rash, nausea, pruritus and back pain. The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Most common adverse reactions (incidence ≥5% of subjects): urticaria, rash, nausea, pruritus and back pain. Allergic reaction (severe hives and a severe rash and pruritus) has occurred following treatment. Recurrent coagulopathy due to envenomation and requiring additional treatment may occur. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 1-877-377-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of CROFAB was evaluated in 289 patients who received CROFAB for crotalid envenomation. Forty-two patients were from two prospective clinical trials in patients who experienced mild to moderate crotalid envenomation; 247 patients were from a retrospective study in patients who experienced mild, moderate or severe envenomation. There also were safety information extracted from literature review of publications on CROFAB that contained patient exposure data. Premarketing Prospective Clinical Trials A total 42 patients received CROFAB for treatment of mild to moderate crotalid envenomation in two clinical studies. The patients were aged 11 to 76 years, and 34 were male and 8 were female. Nineteen patients experienced an adverse reaction for a total of 26 adverse reactions. Adverse reactions involving the skin and appendages (primarily rash, urticaria, and pruritus) were reported in 12 of the 42 patients (see Table 1). One patient discontinued CROFAB therapy due to an allergic reaction. Of the 19 patients who experienced adverse reactions, 3 patients experienced severe or serious adverse reactions. 1 patient who experienced a serious adverse reaction had recurrent coagulopathy due to envenomation, which required re-hospitalization and additional antivenin administration. This patient eventually made a complete recovery. 2 patients had severe adverse reactions that consisted of 1 patient who developed severe urticaria following treatment and 1 patient who developed a severe rash and pruritus several days following treatment. Both patients recovered following treatment with antihistamines and prednisone. Table 1 Incidence of Adverse Reactions by Body System in Premarketing Clinical Trials † Allergic reaction consisted of urticaria, dyspnea and wheezing in 1 patient. Adverse Reaction n=42 Number of Reactions Body as a Whole Back pain 2 Allergic reaction† 1 Serum sickness 1 Skin and Appendages Urticaria 7 Rash 3 Pruritus 2 Subcutaneous nodule 1 Respiratory System Cough 1 Digestive System Nausea 3 Anorexia 1 Hematologic/Lymphatic Coagulation disorder 1 Ecchymosis 1 Musculoskeletal Myalgia 1 Nervous System Nervousness 1 Six of 42 patients experienced an adverse reaction associated with an early serum reaction and 4 experienced an adverse reaction associated with a late serum reaction. Two additional patients were considered to have experienced a late serum reaction by the investigator, although no associated adverse reaction was reported. Serum reactions are defined as reactions associated with CROFAB infusion. They consisted mainly of urticaria and rash, and all patients recovered without sequelae. Table 2 lists the incidence of early and late serum reactions. There were 7 events classified as early serum reactions and 5 events classified as late serum reactions; none was serious. Table 2 Incidence of Early and Late Serum Reactions in Premarketing Clinical Trials ** Allergic reaction consisted of urticaria, dyspnea and wheezing in 1 patient. † Serum sickness consisted of severe rash and pruritus in 1 patient. n=42 Number of Events Early Serum Reactions Urticaria 5 Cough 1 Allergic reaction** 1 Late Serum Reactions Rash 2 Pruritus 1 Urticaria 1 Serum sickness† 1 Postmarketing Retrospective Study This was a retrospective study of data collected from postmarketing use of CROFAB to compare treatment and outcome characteristics between patients with severe envenomation to those with mild to moderate envenomation. A total of 247 patients received CROFAB for treatment of mild, moderate or severe crotalid envenomation. The patients were aged 1 to 91 years, and 206 were male and 41 were female. Of the 247 patients, 209 were classified as mild/moderate (n=181) or severe (n=28), while 38 patients did not have enough data to calculate an initial severity score. There were a total of 36 immediate adverse drug reactions reported in 15 patients (6.1%, n = 247). There were 11 immediate serious adverse events related to CROFAB administration reported in four patients. The events included two episodes each of hypotension and tongue swelling, and one episode each of chest discomfort, angioedema, bronchospasm, wheezing, tracheal edema, dyspnea, and lip swelling. There were 22 immediate non-serious adverse events related to CROFAB administration reported in 12 patients. The events included four episodes each of rash and pruritus, three episodes of urticaria and one episode each of tachycardia, tachypnea, erythema, swelling, hyperhidrosis, dizziness, headache, musculoskeletal chest pain, chills, feeling cold and nervousness. Delayed hypersensitivity reactions were reported for two patients. In one patient, symptoms described as hives, itching and epigastric pressure occurred 6 days post-dosing and were not serious. In the second patient, symptoms were not described in the medical records and therefore were not captured in this study. Recurrent coagulopathy developed in 5 severely envenomated patients and in 6 mild/moderate envenomated patients. In addition, 7 mild/moderate patients experienced delayed-onset coagulopathy. One severely envenomated patient with recurrent coagulopathy experienced medically significant bleeding. Additional Published Clinical Studies Experience From a literature review of nine publications on CROFAB that contained patient exposure data, 15 of 313 (4.8%) patients receiving CROFAB experienced acute hypersensitivity reactions. The most common signs and symptoms associated with these reactions were rash (10 patients) and wheezing (3 patients). Most reactions were mild, resolved after antihistamine therapy, and did not require discontinuation of antivenom therapy. No patient developed a life-threatening hypersensitivity reaction, required intubation, suffered lasting ill-effect or died as a result of CROFAB administration. Follow up data (minimum of six days after treatment) were available in 94 of the 313 patients. Delayed hypersensitivity reactions were reported in 10 cases. The most common signs and symptoms of delayed hypersensitivity were rash (9 patients) and fever (3 patients). Most were mild and treated with antihistamines and steroids. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during the post approval use of CROFAB. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure: Delayed allergic reaction manifested by fever, pruritis and/or rash Delayed or recurrent coagulopathy or thrombocytopenia Failure to achieve initial control Recurrent swelling refractory to treatment Thrombocytopenia refractory to treatment Prolonged hospitalization Bleeding Tremor Treatment failure resulting in death

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For intravenous use only For intravenous use only Initiate administration as soon as possible after snake bite in patients who develop signs of envenomation (e.g. local injury, coagulation abnormality or systemic signs of envenomation) Dose: (2.1) Recommended initial dose is between 4 and 6 vials Observe patient for up to one hour after the initial dose and give an additional 4-6 vial dose as needed to gain initial control of envenomation After initial control is established, administer additional 2-vial doses every 6 hours for 18 hours (total of 3 doses) Administration: (2.2) Reconstitute each vial of CROFAB with 18 mL of 0.9% Sodium Chloride and mix by continuous manual inversion until no solid material is visible in the vial Do not shake Further dilute the entire dose with 0.9% Sodium Chloride to a total volume of 250 mL Infuse each dose intravenously over at least 1 hour 2.1 Dosage Administer CROFAB as soon as possible in patients who develop any signs of envenomation (e.g., local injury, coagulation abnormality or systemic signs of envenomation) to prevent clinical deterioration. CROFAB was shown in clinical studies to be effective when given within 6 hours of snakebite. Antivenin dosage requirements are contingent upon an individual patient’s response. Based on clinical experience with CROFAB, the recommended initial dose is 4 to 6 vials; however, the starting dose may vary from a minimum of 4 vials to a maximum of 12 vials based on clinical judgment and severity of envenomation [3]. Observe the patient for up to 1 hour following completion of the first dose to determine if initial control of envenomation has been achieved. Initial control is achieved when local signs of envenomation are arrested (leading edge of local injury is not progressing), systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal. If initial control is not achieved by the first dose, an additional dose of 4 to 6 vials should be administered repeatedly until initial control of the envenomation syndrome has been achieved. Once initial control has been achieved, additional 2-vial doses of CROFAB every 6 hours for up to 18 hours (3 doses) are recommended. Optimal dosing following the 18-hour scheduled dose of CROFAB has not been determined. Additional 2-vial doses may be administered as deemed necessary by the treating physician, based on the patient’s clinical course. Infusion reactions, such as fever, low back pain, wheezing and nausea, may be related to the rate of infusion and can be controlled by decreasing the rate of administration of the solution [12]. Poison control centers are a helpful resource for individual treatment advice. 2.2 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitute each vial of CROFAB with 18 mL of 0.9% Sodium Chloride (diluent not included) and mix by continuous manual inversion until no solid material is visible in the vial. Do not shake. Further dilute the contents of all of the reconstituted vials to a total volume of 250 mL with 0.9% Sodium Chloride and mix by gently swirling. Use the reconstituted and diluted product within 4 hours. Infuse the dose intravenously over 60 minutes. However, the infusion should proceed slowly over the first 10 minutes at a 25- 50 mL/hour rate with careful observation for any allergic reaction. If no such reaction occurs, the infusion rate may be increased to the full 250 mL/hour rate until completion. Close patient monitoring is necessary.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Animal reproduction studies have not been conducted with CROFAB. It is also not known whether CROFAB can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CROFAB should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations CROFAB contains mercury in the form of ethyl mercury from thimerosal [see Warnings and Precautions, Mercury (5.3)]. Although there are limited toxicology data on ethyl mercury, high dose and acute exposures to methyl mercury have been associated with neurological and renal toxicities. Developing fetuses and very young children are most susceptible and therefore, at greater risk. 8.2 Lactation Risk Summary It is not known whether CROFAB is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when CROFAB is administered to a nursing woman. 8.4 Pediatric Use Thirty-two percent (78/247) of patients studied in a post-marketing retrospective study of CROFAB were 16 years of age or younger (median 8.5 years [range 1 to 16 years]). Initial control of envenomation was achieved in 64/72 (89%) of pediatric patients, which was similar to the initial control rate in adults (103/128, 80%). Changes in severity score, recurrence and incidence adverse reactions were similar between pediatric and adult patients, indicating safety and efficacy in the pediatric population are comparable to that in adults. Limited published clinical experience has not shown that a dosage adjustment for age should be made [14, 15]. CROFAB contains mercury in the form of ethyl mercury from thimerosal [see Warnings and Precautions, Mercury (5.3)]. Although there are limited toxicology data on ethyl mercury, high dose and acute exposures to methyl mercury have been associated with neurological and renal toxicities. Developing fetuses and very young children are most susceptible and therefore, at greater risk. 8.5 Geriatric Use Five percent (13/247) of patients studied in a post-marketing retrospective study of CROFAB were over 65 years of age (median 72 years [range 67 to 91 years]). The efficacy and safety of CROFAB in the geriatric population appears comparable to the overall population.

More information

Category Value
Authorisation number BLA103788
Agency product number 7WZ1744G86
Orphan designation No
Product NDC 50633-110
Date Last Revised 22-06-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder BTG International Inc.