Anavip

Name: Anavip

Pregnancy & Lactation

Pregnancy category: C

Lactation: Unknown if distributed in human breast milk; use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

What should I discuss with my healthcare provider before receiving Anavip (antivenin (Crotalidae) polyvalent)?

If possible before you receive Crotalidae antivenin, tell your doctor if you allergic to any foods, animals, or other allergens. Before treating you with this medicine, your caregivers should know if you are allergic to papaya, papain, pineapples, sheep, horses, dust mites, or latex.

Also tell your doctor if you have:

  • a bleeding or blood clotting disorder such as hemophilia;

  • cancer;

  • congestive heart failure; or

  • an overactive thyroid.

Crotalidae antivenin is made from the blood or plasma of healthy horses or sheep. Animal blood or plasma may contain viruses and other infectious agents. Blood and plasma are tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant.

It is not known whether Crotalidae antivenin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

In an emergency situation it may not be possible to tell your caregivers if you are pregnant or breast-feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medicine.

What happens if I miss a dose?

Because you will receive Crotalidae antivenin in a clinical setting, you are not likely to miss a dose.

Precautions While Using Anavip

Your doctor will check your or your child's progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and does not cause any unwanted effect. Blood tests may be needed to check for unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you or your child has a rash, itching, lightheadedness, dizziness, or fainting, joint or muscle pain, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after you get the injection.

Check with your doctor right away if you or your child has muscle or joint pain, fever, itching, or rash after receiving this medicine. These can be signs and symptoms of a delayed allergic reaction called serum sickness.

This medicine is made from horse plasma. Some horse blood products have transmitted viruses to people who have received them, although the risk is low. Talk to your doctor if you have any symptoms that concern you.

Tell your doctor right away if you or your child has unusual bleeding or bruising, blood in the urine or stool, heavy menstrual bleeding, or nosebleeds after receiving this medicine.

Clinical Studies

Study 1 was a randomized, prospective, open-label, controlled, comparative, multicenter study was conducted in 12 patients aged 18 to 70 years of age with signs of pit viper envenomation6. The subjects received either a licensed pit viper antivenin as an active control, or Anavip. The subjects were dosed until initial control was achieved, followed by maintenance doses. All patients in both treatment groups achieved initial control of local injury and coagulopathy following early antivenin treatment.

In the active control group, at the end of maintenance dosing, 5 of 6 subjects had platelet counts above 150,000/mm3, and all 6 had fibrinogen levels above 150 mg/dL. During the follow-up phase two patients exhibited platelets below 150,000/mm3 and fibrinogen below 150 mg/dL, leading to inpatient management with administration of additional doses (one subject received an additional 6 doses (12 vials) and one subject received an additional 4 doses (8 vials).

In the Anavip arm, at the end of maintenance dosing, 5 of 6 subjects had platelet counts above 150,000/mm3. One subject’s platelets were 114,000/mm3 and were trending upward and all 6 had fibrinogen levels above 150 mg/dL. During the follow-up phase, 5 of 6 subjects had platelet counts above 150,000/mm3, with no downward trend; 1 subject’s platelet counts was 127,000/mm3 on follow-up Day 1, reached 160,000/mm3 on Day 4 and continued trending upward. All 6 subjects in the Anavip group had fibrinogen levels above 150 mg/dL during the follow-up phase. None in the Anavip group required rehospitalization or retreatment with Anavip.

Study 2 was a randomized, prospective, blinded, controlled, comparative, multicenter study, comparing two Anavip regimens with a licensed pit viper antivenin (comparator) conducted in patients with pit viper envenomation at 16 sites in the United States. The study had an in-hospital Acute Treatment Phase that included screening and baseline assessments, initial and maintenance dosing, and an outpatient Follow-up Phase that included 4 follow-up visits on Days 5, 8, 15 and 22.

Patients were randomized in a 1:1:1 ratio to one of three groups: Anavip with Anavip maintenance therapy (Group 1), Anavip with placebo maintenance therapy (Group 2), or Comparator product with Comparator product maintenance therapy (Group 3).

Initial dosing consisted of sequential intravenous (IV) doses infused to achieve initial control. If initial control of envenomation was not achieved, treatment was repeated until initial control was attained. Maintenance dosing (4 vials of Anavip or placebo [normal saline], or 2 vials of comparator product) was initiated 6 hours after the start of the last dose required to achieve initial control, and continued every 6 hours for 3 doses.

The Follow-up Phase began immediately after the third maintenance dose. Patients returned to the clinical site on Days 5, 8, and 15 for scheduled follow-up visits. Patients with ongoing signs of envenomation received 4 vials of Anavip or 2 vials of Comparator product. Dosing was provided as needed until the patient was stabilized. One hundred twenty one (121) patients received blinded study drug and were analyzed for safety and efficacy.

The efficacy endpoint was the proportion of patients experiencing coagulopathic effect as measured on Study Day 5 or Study Day 8. Patients were assessed as experiencing a coagulopathic effect if they had any one of the following: absolute platelet levels < 150,000/mm3 as measured on either Study Day 5 (±1 day) or 8 (±1 day); absolute fibrinogen levels <150 mg/dL as measured on either Study Day 5 (±1 day) or 8 (±1 day); or clinical coagulopathy between end of maintenance dosing and Study Day 5 requiring additional antivenin. The comparison of coagulopathic effect proportions between treatment groups was tested using an exact logistic regression model with terms for treatment and region. Comparisons of the proportion of coagulopathic effect for two levels of Anavip versus Comparator product were performed in the following order: Anavip with Anavip maintenance dose versus Comparator product; then Anavip with Placebo maintenance dose versus Comparator product. The number and percentage of patients who experienced coagulopathic effect is summarized by treatment group in Table 3. The efficacy analysis did not meet the pre-specified statistically defined superiority criterion. However, the percentages of subjects showing prespecified criteria for coagulopathic effect on either Day 5 and/or Day 8 were 10.3% and 5.3% in the Groups 1 and 2 when compared to 29.7% in Group 3 indicating efficacy of Anavip in management of coagulopathic effect in patients with North American rattlesnake envenomation.

Table 3. Comparison of Coagulopathic Effect Rates on Study Day 5 or Study Day 8
Experienced Coagulopathic Effect on Either Day 5 or Day 8, Group 1 (n=39) Anavip/Anavip Group 2 (n=38) Anavip/Placebo Group 3 (n=37) Comparator product
  Yes
No
4 (10.3%)
35 (89.7%)
2 (5.3%)
36 (94.7%)
11 (29.7%)
26 (70.3%)
Treatment Group (vs. Group 3)  Odds Ratio (95% Cl) 0.275(0.058, 1.048) 0.135(0.014, 0.686)

   Cl= confidence interval

FDA conducted a post hoc analysis to assess the outcomes of the patients who presented with or without baseline coagulopathic effect in the three treatment groups. Using the pre-specified criteria for coagulopathic effect, it was found that Anavip/Anavip (Group 1) had the highest percentage of baseline coagulopathic subjects among the three groups [41.5% compared with 17.5% and 32.5% for the Anavip/Placebo (Group 2) and CroFab/CroFab (Group 3), respectively]. Thirty-three percent (33%) of all baseline coagulopathic subjects also experienced coagulopathic effect on either Day 5 or 8, compared to only 6% for baseline non-coagulopathic subjects. Only 18% of the subjects with baseline coagulopathic effect in Group 1 continued to remain coagulopathic at Days 5 or 8 compared to 58% in Group 3 (Table 4).

Table 4. Coagulopathy by Treatment Group and Baseline Coagulopathy
Baseline coagulopathy Experienced coagulopathy on either Day 5 or 8 Anavip/Anavip Anavip/Placebo Comparator product Total
Yes Number of subjects N=17 N=7 N=12 N=36
Yes 3 (17.65%) 2 (28.57%) 7 (58.33%) 12 (33.3%)
No 14 (82.35%) 5 (71.43%) 5 (41.67%) 24 (66.7%)
No Number of subjects N=22 N=31 N=25 N=78
Yes 1 (4.55%) 0 (0%) 4 (16%) 5 (6.4%)
No 21 (95.45%) 31 (100%) 21 (84%) 73 (93.6%)

An exact logistic regression analysis adjusting for baseline coagulopathic effect and region was conducted and showed that treatment effect for both Groups 1 and 2 is statistically significant (Table 5). This analysis provides supportive evidence of the efficacy of Anavip.

Table 5. Comparison Coagulopathic Effect Rates Adjusted for Baseline Coagulopathy
Group 1 (N=39) Anavip/Anavip Group 2 (N=38) Anavip/Placebo
Treatment Group (vs Comparator product)
Odds ration (95% Cl1)
0.184 (0.033, 0.794) 0.121 (0.010, 0.764)

   1Cl= confidence interval

Analysis by snakebite type was performed but was limited due to the number of unknown snakebite types (N=43). However, 57 subjects who were envenomated by rattlesnakes showed more severe coagulopathic effects and resolution of these effects after treatment with Anavip as compared to 21 subjects who were envenomated by copperhead snakes. Efficacy outcomes could not be evaluated in the copperhead snake bite subgroup due to these limited coagulopathic effects.

What Is Anavip?

Crotalidae antivenin is an anti-venom used to treat a person who has been bitten by a poisonous snake such as a rattlesnake or Water Moccasin.

Antivenin (Crotalidae) polyvalent may also be used for purposes not listed in this medication guide.

If possible before you receive this medicine, tell your doctor if you are allergic to any foods, animals, or other allergens.

In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast feeding. Make sure any doctor caring for you afterward knows that you have received this medication.

If possible before you receive Crotalidae antivenin, tell your doctor if you allergic to any foods, animals, or other allergens. Before treating you with this medicine, your caregivers should know if you are allergic to papaya, papain, pineapples, sheep, horses, dust mites, or latex.

Also tell your doctor if you have:

  • a bleeding or blood clotting disorder such as hemophilia;
  • cancer;
  • congestive heart failure; or
  • an overactive thyroid.

Crotalidae antivenin is made from the blood or plasma of healthy horses or sheep. Animal blood or plasma may contain viruses and other infectious agents. Blood and plasma are tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant.

It is not known whether Crotalidae antivenin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

In an emergency situation it may not be possible to tell your caregivers if you are pregnant or breast-feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medicine.

Anavip Side Effects

Get emergency medical help if you have signs of an allergic reaction: hives, itching, redness; wheezing, trouble breathing; feeling light-headed; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel feverish or nauseated, or if you have low back pain or trouble breathing.

Call your doctor at once if you have:

  • easy bruising, unusual bleeding (nosebleeds, bleeding gums, bleeding from an injury);
  • purple or red pinpoint spots under your skin;
  • fever, swollen glands, rash or itching, joint pain, or general ill feeling;
  • heavy menstrual bleeding; or
  • itching, rash, or skin redness several days after you were treated with Crotalidae antivenin.

Common side effects may include:

  • itching;
  • rash;
  • nausea; or
  • back pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Usual Adult Dose for Venomous Snake Bite

Initial dose: 4 to 6 vials, IV, over 60 minutes: at 25 to 50 mL/hour the first 10 minutes - if no allergic reaction, may increase rate to 250 mL/hour

Continue administering 4 to 6 vials, IV, over 60 minutes, every 6 hours for up to 18 hours, until initial control of envenomation is achieved

Maintenance dose (after initial envenomation control is achieved): 2 vials, IV, every 6 hours for up to 18 hours (3 doses); additional 2 vial doses may be given as deemed necessary based on the patient's clinical course

Comments:
-Administer as soon as possible after snakebite in patients with signs of progressive envenomation (e.g. worsening local injury, coagulation abnormality, or systemic envenomation signs).
-Early use (within 6 hours of snakebite) is advised to prevent clinical deterioration and systemic coagulation abnormalities.
-Closely monitor patients for allergic reactions during the infusion.
-Observe the patient for up to 1 hour after the first dose to determine if initial control has been achieved.

Dialysis

Data not available

Other Comments

Storage requirements:
-Refrigerate; do not freeze

Reconstitution/preparation techniques:
-Reconstitute each vial with 18 mL of 0.9% saline.
-Mix by continuous manual inversion until no solid material is visible.
-Do not shake.
-Further dilute the contents of all reconstituted vials in 250 mL of 0.9% saline, mix by gently swirling.
-Use reconstituted product within 4 hours.

General:
-Supportive measures are often used for pain, swelling, hypotension, and wound infections from snakebite.
-Poison control centers are helpful for individual treatment advice.

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