Anavip

Treatment with Crotalidae antivenin should be started as soon as possible after the first appearance of symptoms of a snake bite (fang marks in the skin with swelling or redness and pain, blurred vision, sweating, increased salivation, vomiting, uncontrolled bleeding, trouble breathing, weakness, loss of muscle control, or numbness in the face or body).

Crotalidae antivenin is injected into a vein through an IV. A healthcare provider will give you this injection. Crotalidae antivenin must be given slowly, and the IV infusion can take at least 60 minutes to complete.

This medicine is most effective if given within 6 hours after the snakebite occurred.

You will be watched closely for up to 60 minutes after receiving Crotalidae antivenin, to make sure this medicine is helping your condition.

You may need to receive additional doses if your condition does not improve after the first dose. Once your symptoms are under control, you may be given more doses every 6 hours for up to 18 hours or longer. Your doctor will determine how long to treat you with Crotalidae antivenin.

Venom from a snake bite can increase your risk of bleeding, which can be severe or life-threatening. Contact your doctor or seek emergency medical attention if you have any bleeding that will not stop.

Your doctor will need to check your progress for up to 2 weeks or longer after you are treated with Crotalidae antivenin. You may need to be re-treated with this medicine, or with other drugs that can help your blood to clot.

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.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Anavip® in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Anavip® in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to cresol or
• Allergy to horses or horse blood products—May increase risk for more serious side effects.

For Intravenous use only.

Administer Anavip as soon as possible after rattlesnake bite in patients who develop any signs of envenomation (e.g., local injury, coagulation abnormality, or systemic signs of envenomation).

The amount of antivenin required to treat a snake bitten patient is highly variable owing in part to the venom burden, the potency of the venom and the time to health care presentation. Use supportive measures to treat certain manifestations of rattlesnake envenomation, such as pain, swelling, hypotension, and wound infection. Contact the local poison control centers for additional individual treatment advice.

Prior to initiating treatment perform laboratory analyses, including complete blood count, platelet count, PT, PTT, serum fibrinogen level and routine serum chemistries. Repeat testing at regular intervals to gauge response to therapy and anticipate additional dosing.

Initial Dose: 10 vials

• The initial dose of Anavip is 10 vials.
• Reconstitute the contents of each vial with 10 milliliters (mL) of sterile normal saline. Reconstitution time should be less than one minute when using continuous gentle swirling.
• Inspect the solution visually for particulate matter and discoloration prior to administration. The solution is expected to be clear to yellow/green and opalescent. Do not use if otherwise discolored or turbid.
• Combine the contents of the reconstituted vials promptly and further dilute to a total volume of 250 mL with sterile normal saline. Fluid volumes may need to be adjusted for very small children or infants. Poison Control Centers are a helpful resource for individual treatment advice.
• Infuse intravenously over 60 minutes.

• For the first 10 minutes infuse at a 25-50 mL/hour rate, carefully monitoring for any allergic reactions, including an anaphylactic reactions. Discontinue the infusion if any allergic reaction occurs and institute appropriate emergency treatment. Reassess the risk to benefit before continuing the infusion.
• If no reactions occur, the infusion rate may be increased to the full 250 mL/hour rate until completion. If there is any allergic reaction at any time, stop the infusion, treat accordingly, and reassess the need to continue Anavip.

• Following the completion of infusion, monitor the patient for at least 60 minutes for any allergic reaction and to determine that local signs of envenomation are not progressing (leading edge of local injury not progressing), systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal.
• Discard partially or unused reconstituted and diluted product.

Additional Dosing to Achieve Initial Control

• Administer additional 10 vial doses if needed to arrest the progressive symptoms and repeat every hour. There is no known maximum dose.
• Repeat above steps for initial dose as many times as needed until local signs of envenomation are not progressing, systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal.
• Prepare as described above for initial dose.
• Once initial control has been achieved, observe the patient to determine any need for further dosing, as described below.

Observation and late Dosing

• Monitor patients in a health care setting at least 18 hours following initial control of signs and symptoms. Re-emerging symptoms including coagulopathies may be suppressed with additional 4 vial doses of Anavip as needed. Reconstitute each vial with 10 mL of sterile normal saline. Combine and further dilute to a total of 250 mL. Infuse intravenously over 60 minutes.

3 DOSAGE FORMS AND STRENGTHS

Anavip is supplied as a sterile, lyophilized powder. Each vial contains not more than 120 milligrams (mg) total protein and not less than the indicated number of mouse LD50 neutralizing units:

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

Hypersensitivity

Anavip may cause allergic reactions.

• Patients with known allergies to horse protein are particularly at risk for an anaphylactic reaction. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypertension) occur, discontinue immediately and institute appropriate treatment.
• Monitor patients with follow-up visits for signs and symptoms of delayed allergic reactions or serum sickness (rash, fever, myalgia, arthralgia, pruritus, urticarial rash) and treat appropriately if necessary.

Transmissible Infectious Agents

Anavip is made from equine (horse) plasma and may therefore carry a risk of transmitting infectious agents, e.g., viruses.

Reactions to Cresol

Trace amounts of cresol from the manufacturing process are contained in Anavip. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

6 ADVERSE REACTIONS

The most common adverse reactions observed in more than 2 percent of patients in the clinical trials for Anavip were: pruritus, nausea, rash, arthralgia, peripheral edema, erythema, headache, myalgia, pain in extremity, and vomiting.

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.

A total of 86 patients were treated with Anavip, ranging from 2 to 80 years old. The patient population was comprised of 60 males and 26 females. Patients were monitored for signs and symptoms of adverse reactions, including acute hypersensitivity reactions and serum sickness. Follow-up interviews were conducted at 5, 8, 15 and 22 days after treatment to assess symptoms of ongoing venom effect, serum sickness, and any other adverse reactions.

Table 1 shows the adverse reactions occurring in patients across all clinical trials for Anavip. Seventy six percent (65/86) of patients receiving Anavip reported at least one adverse reaction.

8 USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Anavip. It is also not known whether Anavip can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Anavip should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Anavip is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Anavip is administered to a nursing woman.

Pediatric Use

Twenty-four percent (21/86) of patients studied in clinical trials were 16 years of age or younger (6 patients were 2 years of age to 5 years of age, 15 patients ranged from at least 5 years of age to 16 years of age). None of the pediatric patients in the phase 3 study experienced a recurrent coagulopathic effect. All adverse reactions in the pediatric patients were non-serious. The most frequent adverse reactions among pediatric patients were nausea and vomiting, itching and fever. Thus, the safety and efficacy in the pediatric population was not different from adults.

Geriatric Use

Over 9 percent (8/86) of patients studied in clinical trials were over 65 years of age. The efficacy of Anavip in the geriatric population appears comparable to the overall population.

Anavip is supplied as a sterile lyophilized preparation in a single-use vial. When reconstituted with 10 mL of 0.9% NaCl solution, each vial contains not more than 12 mg per mL of protein, and will neutralize not less 780 times the LD50 of Bothrops asper venom and 790 times the LD50 of Crotalus durissus venom in a mouse neutralization assay.

Each box contains 1 vial of Anavip.

NDC 66621-0790-1

• Store at room temperature (up to 25 ºC (77 ºF)). Brief temperature excursions are permitted up to 40 ºC (104ºF).
• DO NOT FREEZE.
• Discard partially used vials.

After a snakebite, you should avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Other drugs may interact with antivenin (Crotalidae) polyvalent, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Treatment with Crotalidae antivenin should be started as soon as possible after the first appearance of symptoms of a snake bite (fang marks in the skin with swelling or redness and pain, blurred vision, sweating, increased salivation, vomiting, uncontrolled bleeding, trouble breathing, weakness, loss of muscle control, or numbness in the face or body).

Crotalidae antivenin is injected into a vein through an IV. A healthcare provider will give you this injection. Crotalidae antivenin must be given slowly, and the IV infusion can take at least 60 minutes to complete.

This medicine is most effective if given within 6 hours after the snakebite occurred.

You will be watched closely for up to 60 minutes after receiving Crotalidae antivenin, to make sure this medicine is helping your condition.

You may need to receive additional doses if your condition does not improve after the first dose. Once your symptoms are under control, you may be given more doses every 6 hours for up to 18 hours or longer. Your doctor will determine how long to treat you with Crotalidae antivenin.

Venom from a snake bite can increase your risk of bleeding, which can be severe or life-threatening. Contact your doctor or seek emergency medical attention if you have any bleeding that will not stop.

Your doctor will need to check your progress for up to 2 weeks or longer after you are treated with Crotalidae antivenin. You may need to be re-treated with this medicine, or with other drugs that can help your blood to clot.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

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

Applies to antivenin (crotalidae) polyvalent: intravenous powder for solution

Along with its needed effects, antivenin (crotalidae) polyvalent (the active ingredient contained in Anavip) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking antivenin (crotalidae) polyvalent:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• difficulty with moving
• flushing or redness of the skin
• itching skin or rash
• muscle pain or stiffness
• nausea
• pain in the joints
• tingling of the hands or feet
• unusual weight gain or loss
• unusually warm skin
• vomiting

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chills
• confusion
• decreased urination
• dizziness
• dry mouth
• fainting
• fever
• increase in heart rate
• lightheadedness
• pinpoint red spots on the skin
• rapid breathing
• sunken eyes
• thirst
• unusual bleeding or bruising
• unusual tiredness or weakness
• wrinkled skin

Some side effects of antivenin (crotalidae) polyvalent may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Headache
• pain in the arms or legs

• Fear or nervousness
• trouble sleeping

Data not available

Animal studies have not been conducted. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use is not recommended unless clearly needed. US FDA pregnancy category: C Comments: -This product contains ethyl mercury from thimerosal. -Limited data on high dose and acute exposures to methyl mercury associate it with neurological and renal toxicities. -Developing fetuses and very young children are more susceptible to methyl mercury toxicity.