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Recuvyra

This page contains information on Recuvyra for veterinary use.
The information provided typically includes the following:
  • Recuvyra Indications
  • Warnings and cautions for Recuvyra
  • Direction and dosage information for Recuvyra

Recuvyra

This treatment applies to the following species:
Manufacturer: Elanco

(fentanyl)

transdermal solution

For Topical Application in Dogs Only

Opioid Analgesic

NOT FOR INJECTION

50 mg/mL (500 mg/10 mL)

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Warning

Abuse Potential:

RECUVYRA contains fentanyl, a high concentration ì-opioid receptor agonist (50 mg/mL) and is a Class II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Class II opioid substances have the highest potential for human abuse and criminal diversion. The high concentration of RECUVYRA may be a particular target for human abuse. Fentanyl has additive CNS depressant effects when used with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Fatal fentanyl overdoses in humans are due to respiratory depression.

The risk of abuse by humans should be considered when storing, administering, and disposing of RECUVYRA. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (suicidal depression).

Risk Minimization and Action Plan:

This product is distributed under a Risk Minimization Action Plan (RiskMAP) and its use is limited to certified veterinarians.

Human Safety:

SECONDARY EXPOSURE TO FENTANYL IN CHILDREN AND ADULTS:

Strict adherence to the requirements of the RiskMAP and the INSTRUCTIONS FOR USE provided in this product insert is imperative in order to reduce the potential of secondary exposure to fentanyl from RECUVYRA treated skin.

The dog should be isolated from children for 72 hours (3 days)

from the time of RECUVYRA application to the dog.

If a child comes in direct contact with the dog within 72 hours (3 days) from the time of RECUVYRA application to the dog, the exposed part of the child’s body should not contact the child’s mouth or eyes, and the area should be washed with soap and water.

If a child’s tongue comes in contact with the dog, or another part of the child’s body comes in contact with the dog and is then placed in the mouth, it is possible for fentanyl to enter the bloodstream; this is a medical emergency and the child should be seen immediately by a physician.

Adults should avoid contact with the application site for 72 hours (3 days) following the application of RECUVYRA to the dog. Within this period, any part of the body that directly contacts the application site should be washed with soap and not inserted into the mouth.

The antidote for human exposure to RECUVYRA transdermal solution is an opioid reversal agent such as naltrexone or naloxone.

Animal Safety:

Individual dogs especially sensitive to the effects of fentanyl may develop gastrointestinal stasis with an increased risk of bacterial overgrowth, accompanied by pronounced sedation, and decreased intake of food and water. Dehydration and elevations in hematocrit, albumin, and fibrinogen may occur. Feces, if present, could be soft and contain blood. In the event of severe gastrointestinal stasis, an opioid reversal agent should be administered to the dog (see PRECAUTIONS) with intravenous fluids and other supportive measures.

RECUVYRA is contraindicated for dogs with diseased or injured dorsal scapular epidermis, dogs expected to have mild or absent perioperative pain, dogs with paralytic ileus, and dogs with known hypersensitivity to fentanyl.

See Contraindications, Warnings: Human and Animal Safety, and Precautions for detailed information.

RISK MINIMIZATION & ACTION PLAN

The RECUVYRA Risk Minimization Action Plan (RiskMAP) provides educational materials to the veterinarian, veterinary staff, and the dog owner explaining the risks and proper use of RECUVYRA. Once it is documented that the dog owner has read and understood the materials by signing the client information sheet, the drug can be applied to the patient. Veterinarians are expected to report all serious adverse events that occur in animals or humans to the manufacturer (see WARNINGS).

RECUVYRA is only for use in dogs, and available only through a restricted distribution program limited to certified distributors that are trained to distribute RECUVYRA under the conditions of the RiskMAP. RECUVYRA can only be received and administered by veterinarians through the restricted distribution program because of the potential for human abuse and safety risks associated with its use in dogs.

Description

RECUVYRA is a volatile liquid transdermal solution intended for topical application that provides continuous, systemic delivery of a potent analgesic opioid. RECUVYRA is a clear, colorless to light yellow solution that contains 5% w/v (50 mg/mL) fentanyl as the active pharmaceutical ingredient in alcohol and octyl salicylate. Fentanyl is a µ (mu) opioid receptor agonist. Once applied to the skin, RECUVYRA is a rapid drying formulation resulting in fast dermal absorption and sequestration of fentanyl in the stratum corneum.

Recuvyra Indications

RECUVYRA is indicated for the control of postoperative pain associated with surgical procedures in dogs.

DOSAGE AND ADMINISTRATION

NOT FOR INJECTION

The dosage of RECUVYRA is 1.2 mg/lb (2.7 mg/kg) applied topically to the dorsal scapular area 2 to 4 hours prior to surgery. A single application provides analgesia for 4 days. Use the provided syringe and applicator tips.

Apply RECUVYRA only once. Accumulation of fentanyl following repeated administration could result in severe adverse reactions, including death (see ANIMAL SAFETY).

Do not dispense RECUVYRA for administration at home by the pet owner.

RECUVYRA should only be handled and administered to dogs by hospital staff specially trained in its use. To prevent human adverse reactions or abuse, at least 2 trained administrators should be present during administration of RECUVYRA. Wear impermeable latex or nitrile gloves, protective glasses and a laboratory coat to prevent direct contact with human skin, eyes or mucosa when handling and/or applying the solution. Do not administer RECUVYRA outside of the hospital setting.

Use only the syringes provided and do not store RECUVYRA in the syringe. Use of syringes incompatible with RECUVYRA will result in inaccurate dosing or human exposure (see Instructions for Use for details regarding drug application and restraint during drying time).

RECUVYRA DOSE

(1.2 mg/lb; 2.7 mg/kg) in mL based on body weight

POUNDS OF BODY WEIGHT

DOSE (mL)

KILOGRAMS OF BODY WEIGHT

6 to 9.3*

0.2

2.7 to 4.2

9.4 to 13.4

0.3

4.3 to 6.1

13.5 to 17.6

0.4

6.2 to 8

17.7 to 21.8

0.5

8.1 to 9.9

21.9 to 25.9

0.6

10 to 11.7

26 to 30.1

0.7

11.8 to 13.6

30.2 to 34.3

0.8

13.7 to 15.5

34.4 to 38.4

0.9

15.6 to 17.4

38.5 to 42.6

1

17.5 to 19.3

42.7 to 46.8

1.1

19.4 to 21.2

46.9 to 50.9

1.2

21.3 to 23.1

51 to 55.1

1.3

23.2 to 25

55.2 to 59.3

1.4

25.1 to 26.9

59.4 to 63.4

1.5

27 to 28.8

63.5 to 67.6

1.6

28.9 to 30.6

67.7 to 71.8

1.7

30.7 to 32.5

71.9 to 75.9

1.8

32.6 to 34.4

76 to 80.1

1.9

34.5 to 36.3

80.2 to 84.3

2

36.4 to 38.2

84.4 to 88.4

2.1

38.3 to 40.1

88.5 to 92.6

2.2

40.2 to 42

92.7 to 96.8

2.3

42.1 to 43.9

96.9 to 100.9

2.4

44 to 45.8

101 to 105.1

2.5

45.9 to 47.7

105.2 to 109.3

2.6

47.8 to 49.6

109.4 to 113.4

2.7

49.7 to 51.4

113.5 to 117.6

2.8

51.5 to 53.3

117.7 to 121.8

2.9

53.4 to 55.2

121.9 to 125

3

55.3 to 57

* RECUVYRA cannot be accurately dosed in dogs less than 6 pounds of body weight. The average dose in each weight band is approximately 2.7 mg/kg, except for the lowest weights, that average slightly higher.

Apply up to 1/2 mL onto the skin without moving the applicator tip. If the calculated volume is greater than 1/2 mL, reposition the applicator tip at least 1 inch from the initial site and apply up to 1/2 mL. Repeat the reposition and application steps until the entire calculated volume has been applied to the dog. Restrain the dog for a full 2 minutes and avoid contact with the application site for 5 minutes to allow complete drying of the solution (SEE INSTRUCTIONS FOR USE).

INSTRUCTIONS FOR USE

RECUVYRA should only be handled and administered to dogs in a clinic setting by hospital staff specially trained in its use. To prevent human adverse reactions or abuse, at least 2 trained administrators should be present during administration of RECUVYRA.

COMPONENTS:

STEP 1:

PREPARATION OF THE HANDLER

Wear impermeable latex or nitrile gloves, protective glasses and a laboratory coat to prevent direct contact with human skin, eyes or mucosa when handling and/or applying the solution.

STEP 2:

COMPLETELY REMOVE THE SHRINK WRAP COVER FROM THE VIAL

Grasp the edge of the shrink wrap at the top of the vial and pull to remove.

STEP 3:

REMOVE THE PLASTIC PROTECTIVE COVER FROM THE VIAL CAP

Grasping the vial, pry the cover off the vial cap by hand.

STEP 4:

ATTACH THE NEEDLELESS ADAPTOR TO THE VIAL

Place the vial upright on a firm, stable surface during placement and application of the needleless adaptor. Center the needleless adaptor directly over the top of the vial. Applying gentle, even pressure, press the needleless adaptor onto the vial until it is seated. Once seated, do not remove the needleless adaptor.

On the vial where it states, DISCARD AFTER, write the date that is 30 days from the date that the needleless adaptor was applied. Store vial upright with the needleless adaptor attached.

STEP 5:

WITHDRAW DRUG FROM THE VIAL

To withdraw RECUVYRA from the vial, press the syringe tip into the center of the needleless adaptor and gently turn syringe approximately 1/4 turn clockwise until fully seated. Invert vial and pull back on syringe plunger until the appropriate volume is withdrawn. It may be necessary to evacuate air from the syringe back into the vial. To accurately withdraw the correct amount, align the top of the O-ring on the syringe plunger with the appropriate tick mark on the syringe barrel. To remove the syringe from the adaptor, turn the vial into the upright position, grasp the needleless adaptor, turn the syringe 1/4 turn counterclockwise and remove the syringe.

STEP 6:

ATTACH APPLICATOR TIP TO SYRINGE

Attach the applicator tip to the syringe by turning the applicator tip 1/3 turn clockwise.

STEP 7:

SITE PREPARATION

It is not necessary to clip the hair over the application site. However, in dogs with thick haircoats, close clip the hair on the dorsal scapular area prior to application to ensure direct contact of RECUVYRA with the skin. The application site should be free of gross debris and the skin should be intact and free from disease or injury.

STEP 8:

APPLY RECUVYRA TO THE DOG

Place applicator tip at an approximate 45º angle directly onto the skin in the dorsal scapular area. It is important that both tips make direct contact with the skin.

Apply up to 1/2 mL onto the skin without moving the applicator tip. If the calculated volume is greater than 1/2 mL, reposition the applicator tip at least 1 inch from the initial site and apply up to 1/2 mL. Repeat the reposition and application steps until the entire calculated volume has been applied to the dog.

Restrain the dog for a full 2 minutes and avoid contact with the application site for 5 minutes to allow complete drying of the solution.

Dispose of the used syringe/applicator tip as a unit in an appropriate container. Disposal should comply with Drug Enforcement Agency (DEA) guidelines.

STORAGE AND DISCARD:

Once broached with the needleless adaptor, store the vial upright at controlled room temperature, 20 - 25°C (68 - 77°F), with the needleless adaptor attached.

RECUVYRA is a Class II opioid (see WARNINGS, Human Safety: Drug abuse, addiction and diversion of opioids). Store in a locked, substantially constructed cabinet according to DEA and local controlled substance guidelines.

Discard broached vials after 30 days. Any unused or expired vials must be destroyed by a DEA registered reverse distributor; for further information call 1-888-545-5973.

Contraindications

Do not apply RECUVYRA to skin that is diseased or injured.

Do not administer RECUVYRA to anatomic areas other than the dorsal scapular area because absorption characteristics may be different.

Do not administer RECUVYRA to dogs where postoperative pain is expected to be mild or absent.

Do not administer RECUVYRA to dogs that have or are suspected of having paralytic ileus.

Do not administer RECUVYRA to dogs that are hypovolemic or debilitated.

Do not administer RECUVYRA to dogs with a known hypersensitivity to fentanyl.

Do not administer a second dose of RECUVYRA. Accumulation of fentanyl following repeated administration could result in severe adverse reactions, including death (see ANIMAL SAFETY).

Do not administer RECUVYRA to any other species; it is intended for use in dogs only. Safe and effective concentrations of fentanyl are dependent on appropriate absorption from skin, and the absorption characteristics of skin vary greatly between species. The safety of RECUVYRA in cats, horses, or other species has not been evaluated.

WARNINGS

Human Safety:

Not for use in humans. Keep out of reach of children. Avoid unprotected contact with application site for 72 hours.

SECONDARY EXPOSURE TO FENTANYL: Strict adherence to the requirements of the RiskMAP and the INSTRUCTIONS FOR USE provided in this product insert is imperative in order to reduce the potential of secondary exposure to fentanyl from RECUVYRA treated skin.

Adult Human User Safety while handling and applying RECUVYRA in the Hospital:

Two trained staff for administration:

Do not dispense RECUVYRA for administration at home by the pet owner. RECUVYRA should only be handled and administered to dogs by hospital staff specially trained in its use. To prevent human adverse reactions or abuse, at least 2 trained administrators should be present during administration of RECUVYRA.

Protective covering:

To prevent direct contact of RECUVYRA with human skin or mucous membranes when handling and/or applying the solution, wear impermeable latex or nitrile gloves, protective glasses and a laboratory coat. To avoid inadvertent contamination of other humans or animals, remove and appropriately dispose of protective garments after RECUVYRA minimum drying time of 5 minutes.

Mucous membrane or eye contact during administration:

Direct contact of RECUVYRA with the eyes, oral cavity or mucous membranes of dogs or humans could result in systemic, clinically relevant fentanyl concentrations. If accidental eye, oral or other mucous membrane contact is made during administration, flush the area with water and seek immediate medical attention.

Skin contact during administration:

If human skin is accidentally exposed to RECUVYRA, wash the exposed area with soap and water and seek medical attention immediately. Accidental exposure could cause adverse reactions.

Drying time:

Following application to the dog, allow a minimum drying time of 5 minutes. As a precaution, hospital staff responsible for handling the dog prior to, during, and after surgery, should wear gloves. All others (including owners) should avoid contact with the application site for 72 hours following application. Within this period, any part of the body that directly contacts the application site should be washed with soap and water and not placed in the mouth.

User Safety following discharge of the dog to the owner:

Adult exposure:

Adults should avoid contact with the application site for 72 hours (3 days) following the application of RECUVYRA to the dog. Within this period, any part of the body that directly contacts the application site should be washed with soap and not placed in the mouth.

Child exposure:

The dog should be isolated from children for 72 hours (3 days) from the time of RECUVYRA application to the dog.

If a child comes in direct contact with the dog within 72 hours (3 days) from the time of RECUVYRA application to the dog, the exposed part of the child’s body should not contact the child’s mouth or eyes, and the area should be washed with soap and water.

If a child’s tongue comes in contact with the dog, or another part of the child’s body comes in contact with the dog and is then placed in the mouth, it is possible for fentanyl to enter the bloodstream; this is a medical emergency and the child should be seen immediately by a physician.

Drug abuse, addiction and diversion of opioids:

RECUVYRA contains fentanyl, a µ-opioid agonist and a Class II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and may be subject to misuse, and criminal diversion. RECUVYRA should be handled appropriately to minimize the risk of diversion, including restriction of access, the use of accounting procedures, and proper disposal methods, as appropriate to the clinical setting and as required by law.

Physician information:

Fentanyl is a µ (mu) opioid receptor agonist (50 mg/mL). The antidote for human exposure to RECUVYRA is an opioid reversal agent such as naltrexone or naloxone. In the case of an emergency, provide the physician with the package insert and Client Information Sheet.

Animal Safety:

Individual dogs sensitive to the effects of fentanyl may develop pronounced sedation, decreased food and water intake and gastrointestinal (GI) stasis, which may increase the risk of bacterial overgrowth. Dehydration and elevations in hematocrit, albumin and fibrinogen may occur. Feces, if present, could be soft and contain blood. If severe GI stasis occurs, the dog should be reversed with naloxone (see PRECAUTIONS) and administered supportive intravenous fluids.

RECUVYRA has not been evaluated in dogs with respiratory disorders, cardiovascular disease, renal disease, or hepatic disease.

Opioid effects, including adverse reactions, may last for 7 days beyond administration in some dogs. To prevent potential overdose and severe adverse reactions, do not administer other opioids within 7 days of RECUVYRA administration.

During general anesthesia following administration of RECUVYRA, dogs should be continuously monitored and facilities should be available for the maintenance of a patent airway, artificial ventilation, IV fluids, and oxygen supplementation.

Hypothermia may be severe and prolonged (greater than 24 hours) necessitating the use of an external heat source during surgery, throughout recovery, and after recovery from anesthesia.

PRECAUTIONS

The concomitant use of RECUVYRA with other CNS depressants (sedatives, hypnotics, general anesthetics, phenothiazines, and skeletal muscle relaxants) may cause respiratory depression, hypothermia, bradycardia, hypotension, and profound sedation. When such concomitant therapy is used, the doses of these agents should be reduced.

Fentanyl is a potent anesthetic sparing drug. To avoid anesthetic overdose, anesthetic agents should be administered to effect in dogs treated with RECUVYRA.

RECUVYRA may result in hypothermia, hypoventilation, hypotension, and bradycardia during anesthesia. Rectal temperature, pulse rate, respiratory rate, oxygen saturation, heart rhythm and blood pressure should be monitored during anesthesia.

Dogs may need longer post-surgical monitoring because of hypothermia or prolonged sedation due to RECUVYRA (see ADVERSE REACTIONS).

RECUVYRA may cause prolonged physiological effects (sedation, respiratory depression, hypothermia, bradycardia, and hypotension) lasting longer than 24 hours. Clinical effects (diarrhea, vomiting, anorexia) could also worsen on the day after surgery. Some dogs may need longer hospitalization, monitoring and appropriate treatment.

Moderate or severe sedation can last up to 2 days after dosing. Dogs must not be discharged to owners until post-operative sedation is mild or absent and dogs are drinking water and eating on their own at an appropriate level for the condition that required surgery.

Emergency administration of naloxone at 0.04 mg/kg may be used to reverse serious adverse reactions associated with RECUVYRA. Administer the reversal agent slowly to avoid abrupt increases in blood pressure and catecholamine levels1. Reversal should occur rapidly (1-2 minutes); however, the duration of action of naloxone is variable (1-3 hours)2. The effects of RECUVYRA could last longer than the effects of the opioid reversal agent.

Fentanyl is a substrate for both the cytochrome P450 3A12 in dogs and the p-glycoprotein membrane efflux transporter≥. Therefore, the concomitant use of RECUVYRA with drugs that inhibit these systems, such as ketoconazole or ivermectin, or the use of this drug in dogs with defective p-glycoprotein4, could result in higher than expected concentrations of fentanyl in the plasma and/or the brain, resulting in a potential increase in adverse reactions (see CLINICAL PHARMACOLOGY).

RECUVYRA has not been evaluated in dogs younger than 6 months of age or in geriatric dogs.

RECUVYRA has not been evaluated for use in breeding, pregnant, or lactating dogs.

ADVERSE REACTIONS

In two randomized multi-centered, double-masked, active-controlled field studies across 25 investigative sites, 502 dogs had orthopedic or soft tissue surgery and were allotted to RECUVYRA (N=249) or oxymorphone hydrochloride (N=253). No RECUVYRA-treated dogs were removed from the study due to adverse reactions under anesthesia. The following adverse reactions were reported in RECUVYRA-treated dogs:

ADVERSE REACTIONS DURING ANESTHESIA:

Adverse Reaction*

RECUVYRA (N=249)

Tachypnea (> 20 breaths/min)

158 (63%)

Bradypnea (< 10 breaths/min)

116 (47%)

Hypertension

37 (15%)

Hypotension

32 (13%)

Tachycardia (> 180 beats/min)

26 (10%)

Hypothermia (< 95°F)

23 (9.2%)

Bradycardia (< 50 beats/min)

9 (3.6%)

Pyrexia (> 102.5°F)

3 (1.2%)

Cardiac Arrhythmia

2 (0.8%)

Reduced Oxygen Saturation of Hemoglobin (pulse oximetry < 85%)

2 (0.8%)

*Physiological adverse reactions occurred during general anesthesia and were included if there was at least one excursion outside the normal anesthetic range at any 5 minute interval during the entire duration of anesthesia.

ADVERSE REACTIONS FROM EXTUBATION THROUGH 96 HOURS AFTER SURGERY:

Adverse Reactions:

RECUVYRA (N=249)

Day 0*

N (%)

Day 1

N (%)

Day 2

N (%)

Day 3

N (%)

Day 4

N (%)

Sedation

(moderate or severe)

123 (49%)

8 (3.2%)

1 (0.4%)

0 (0%)

0 (0%)

Diarrhea

1 (0.4%)

5 (2%)

2 (0.8%)

1 (0.4%)

0 (0%)

Emesis

0 (0%)

4 (1.6%)

2 (0.8%)

2 (0.8%)

0 (0%)

Hypothermia

4 (1.6%)

10 (4%)

0 (0%)

0 (0%)

0 (0%)

Pyrexia

0 (0%)

0 (0%)

1 (0.4%)

1 (0.4%)

0 (0%)

Anorexia

0 (0%)

2 (0.8%)

1 (0.4%)

0 (0%)

0 (0%)

Death

0 (0%)

0 (0%)

0 (0%)

1 (0.4%)

0 (0%)

* Day 0 is the period following extubation on the day of the surgical procedure.

RECUVYRA-treated dogs that were moderately or severely sedated on the day of surgery ranged between 49% at 1 hour post-extubation, 7% at 12 hours post-extubation, and 3% by 24 hours post-extubation. All dogs were mildly or not sedated from 60 hours through 96 hours following surgery.

One 13 year old dog in the fentanyl group was found dead three days after surgery. The dog had a history of vomiting for 4 days prior to the study. Necropsy revealed the cause of death was bacterial pneumonia from repeated vomition. The death was not attributed to fentanyl. One oxymorphone-treated dog died during the study and the death was the result of pulmonary embolism and stroke.

To report suspected adverse drug events, for technical assistance, or to obtain a Material Safety Data Sheet (MSDS), contact Elanco Animal Health at 1-888-545-5973.

For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/AnimalVeterinary/SafetyHealth

INFORMATION FOR DOG OWNERS

Prior to administration with RECUVYRA, dog owners should understand the safety outcomes that could affect them, their family, and their dog. A client information sheet should be discussed and sent home with every dog treated with RECUVYRA. The RECUVYRA RiskMAP program considers the client information sheet as an informed consent form for the dog owner and contains a signature line which should be signed prior to use to document that the dog owner has read and understood the client information sheet.

The owner should be able to isolate the dog from family members, especially children, for several days after discharge. Contact or suspected contact in children could result in potential adverse reactions associated with systemic fentanyl blood levels and should be treated as a medical emergency.

Adverse reactions in the dog may include excessive sedation, decreased appetite, vomiting, and diarrhea. Serious adverse reactions, including death, can occur if prolonged lack of food and water intake and sedation are not addressed with supportive care. Owners should be advised to contact their veterinarian immediately if these signs occur after the dog returns to the home environment (see Client Information Sheet).

CLINICAL PHARMACOLOGY

Fentanyl exerts its analgesic action by binding to and activating µ (mu) opioid receptors that are predominantly found in the pain regulating areas of the brain and spinal cord. The analgesic effects of RECUVYRA are related to the resulting fentanyl blood concentration achieved following application. Once applied to the skin, solvent evaporation results in super-saturation of both a penetration enhancer and fentanyl. At the moment of drying (approximately 2 - 5 minutes following application), rapid dermal absorption and sequestration of fentanyl into the stratum corneum occurs. From the stratum corneum, fentanyl is absorbed into the bloodstream. Because RECUVYRA is not a device like a dermal patch, external thermal heat pads or warm water circulating blankets may be used during or following anesthesia.

In dogs, following intravenous and subcutaneous administration, fentanyl citrate is highly metabolized, with metabolites recovered in the urine and feces5. Fentanyl metabolism has been associated with the cytochrome P450 isoform CYP3A12 in dogs6. In mice lacking P-glycoprotein (P-gp), the maximum fentanyl analgesic effect was increased and prolonged compared to mice with functional P-gp7. P-gp is involved in the active efflux of fentanyl out of the central nervous system, preventing excessive accumulation of fentanyl in the brain. Therefore, dogs with compromised P-gp could potentially experience a greater magnitude and duration of analgesic activity with an increased risk of adverse reactions.

Unlike parenteral injections of fentanyl citrate in dogs where the terminal half-life of fentanyl is determined by the elimination rate, fentanyl from RECUVYRA exhibits absorption-dependent (flip-flop) pharmacokinetics. The absorption rate of fentanyl from skin is much slower than the elimination rate from blood and therefore the primary factor responsible for prolonged fentanyl blood concentrations is extended absorption. Some RECUVYRA can remain under the skin, slowly moving to the blood for up to 1 week.

Pharmacokinetic parameters were calculated from 215 dogs undergoing orthopedic or soft tissue surgery. The mean plasma fentanyl concentration from time 0 through 96 hours post-dose administration was 1.32 ng/mL (Figure 1).

PHARMACOKINETIC PARAMETERS IN A TYPICAL CANINE PATIENT

Terminal half-life

Time to 0.5 ng/mL

Time to 1.0 ng/mL

Cmax

tmax

tlag

74.0 hrs

1.6 hrs

3.08 hrs

1.83 ng/mL

13.6 hrs

0.552 hrs

Figure 1 - Plasma fentanyl concentrations over approximately 4 days following a single RECUVYRA administration, 2 to 4 hours prior to orthopedic or soft tissue surgery (n = 215 dogs). The shaded area is the range of expected plasma fentanyl concentrations in 90% of dogs.

EFFECTIVENESS

In two randomized multi-centered, double-masked, active-controlled field studies across 25 investigative sites, dogs were randomized to RECUVYRA group (N = 249) or opioid active control group (oxymorphone hydrochloride; N = 253 dogs). Dogs in the RECUVYRA group received a single, topical application at a dose of 1.2 mg/lb (2.7 mg/kg) onto the dorsal scapular skin 2 - 4 hours prior to orthopedic or soft tissue surgery. Acepromazine was the most commonly used preanesthetic. Surgeries included cruciate ligament repair, ovariohysterectomy, lateral ear resection, laparotomy, liver biopsy, kidney removal, and tumor removal. Pain was quantified by a trained observer for 96 hours following surgery. At any time point, if the dog’s pain was scored as inadequately controlled, the dogs were considered treatment failures and received supplemental analgesia. Any dogs given an emergency opioid reversal agent for adverse reactions were also considered treatment failures. A total of 21 dogs were treatment failures (4 in the RECUVYRA group and 17 in the active control group). No RECUVYRA-treated dogs were removed due to adverse reactions. The 4 RECUVYRA-treated treatment failures were withdrawn due to inadequate pain control between 1 and 6 hours post-extubation. A non-inferiority evaluation of the upper bound margin of difference between RECUVYRA and active control treatment failure rates over 96 hours demonstrated that RECUVYRA was non-inferior to the active control. Therefore RECUVYRA was effective in controlling pain associated with orthopedic and soft tissue surgery.

ANIMAL SAFETY

In a 16 week laboratory animal safety study, RECUVYRA was administered to young, healthy, adult mongrel dogs at 0 mg/kg (2 dogs), 2.6 mg/kg (8 dogs), 5.2 mg/kg (4 dogs) and 7.8 mg/kg (4 dogs). Doses correspond to 0, 1, 2, and 3 times the dose respectively, and were administered every 7 days for 16 weeks. All doses were applied to the dorsal scapular area. There were no deaths during the study. Sedation was observed with greater frequency and severity in the 5.2 and 7.8 mg/kg groups than in 2.6 mg/kg group. In the 2.6 mg/kg group, moderate sedation was noted in 2 dogs on day 1 and in a single dog on days 2, 14, and 56. Otherwise, sedation was mild or absent. Profound sedation was observed in a single dog in the 5.2 and 7.8 mg/kg groups on days 1-3. The increase in the mean sedation scores was greater during the first few dose intervals than in the subsequent dose intervals, showing the development of tolerance to the sedative effects of RECUVYRA. Evidence of tolerance to RECUVYRA’s effects on heart rate (HR) or respiratory rate (RR) were not definitive; however, the largest decreases in HR and RR occurred after the first dose, generally lessening over time with subsequent doses.

Dogs received supportive therapy as needed during the study. Canned food, towels, or fluid therapy were provided to some dogs (including the 2.6 mg/kg dose group) to prevent weight loss, hypothermia, or moderate sedation. The day after dosing showed the greatest overall decreases in body temperature. By the second day after dosing, the lowest temperature noted in the 2.6 mg/kg group during the 16 week study was 99.1°F. Dogs in the 2.6 group did not receive any temperature related supportive therapy; some dogs in the 5.2 and 7.8 mg/kg groups received thermal support during the study (hot water bottles, heated pads). Dogs had bradycardia (<70 bpm) and moderate sedation on the day of dosing and/or the first day after dosing. In treated groups (including 2.6 mg/kg dogs), HR were lower on the day after dosing compared to 12 hours after the administration of fentanyl. HR decreases did not require treatment and were not severe in the 2.6 mg/kg group. Decreases in RR was seen in all treated groups but bradypnea (RR <10) was not seen. The lowest RR in the 2.6 and 7.8 mg/kg groups was 12 breaths per minute (bpm); the lowest RR in the 5.2 mg/kg group was 16 bpm.

Diarrhea was more frequently observed in fentanyl-treated dogs; however, control dogs also had diarrhea. Six dogs had blood in the stool (described as hemorrhagic diarrhea, tarry stool), including 2 dogs in the 2.6 mg/kg dose group. Four of the 6 dogs with blood in the stool had mild elevations in WBC (13 dogs overall had increases in WBC). Four dogs had elevations during week 1 (0, 2.6, and 5.2 mg/kg), and 2 dogs during week 2 (0 and 7.8 mg/kg).

Inappetance (not due to excessive sedation) and weight loss were seen frequently in the treated dose groups. Body weights dropped initially, through the first to second weeks, returning toward baseline by week 5. In the 2.6 mg/kg group (8 dogs), weight loss during the first two weeks ranged from 5.2-15.8% of initial body weight (compared to 1.7-6.5% in the 2 control dogs). Five of 8 lost 5-<10%; 2 dogs lost 10-<15%; and 1 dog lost 15.8% of body weight compared to baseline body weights.

Abnormalities associated with increased WBC, decreased HGB (hemoglobin), and decreases in MCHC (mean corpuscular hemoglobin concentration) were mild, occurring in the control dogs and all dose groups including the 2.6 mg/kg group. Gross necropsy findings for all treatment groups did not reveal any treatment related findings and no histopathologic findings were reported in the 2.6 mg/kg group.

Fentanyl-related hepatic changes consisted of brown pigmentation in 1 dog from the 5.2 mg/kg and 2 dogs from the 7.8 mg/kg group, focal granulomas in 1 dog from the 7.8 mg/kg group, and single cell necrosis identified in 1 dog from the 7.8 mg/kg group; all changes were considered reversible.

In another safety study, RECUVYRA was administered to 32 healthy adult mongrel dogs (8 dogs per group) at 0 mg/kg, 2.6 mg/kg, 5.2 mg/kg, and 7.8 mg/kg as a topical application to the ventral abdomen every 4 days for a total of 3 doses. Application to the ventral abdomen results in approximately 30% greater exposure with similar peak exposure, compared to dorsal scapular application.

Three dogs died as a result of RECUVYRA administration. Two dogs died on days 4 and 7 (5.2 mg/kg group), and 1 dog died on day 5 (7.8 mg/kg group), all between the second and third doses. Death was due to endotoxic shock as a result of severe gastrointestinal stasis complicated by continued hypothermia, severe dehydration, prolonged sedation, low HR and RR, and elevated clotting parameters.

Sedation varied from slight to profound within all 3 treated groups. Sedation scores were highest during the second dose period and occurred more quickly after the second and third doses. In the 2.6 mg/kg group, 3 dogs showed no or slight sedation, 5 dogs showed moderate, with 2 (of these 5) showing profound sedation. Most dogs in the 5.2 mg/kg and 7.8 mg/kg groups remained moderately to profoundly sedated.

Heart rates and respiratory rates began decreasing within 4 hours of dosing. Respiratory rates had a downward trend with each subsequent dose. Lowest heart rates in the 2.6, 5.2, and 7.8 mg/kg groups were 28, 16, and 28 beats per minute, and the lowest respiratory rates were 8, 4, and 4 breaths per minute. ECG findings in treated dogs included bradycardia and increases in PR and QT intervals. One dog in the 5.2 mg/kg group showed secondary atrioventricular (AV) block.

In the 2.6 mg/kg group, dogs became hypothermic (body temperature <98°F) within 12 hours after the first dose. After the second and third doses, some dogs (in all treatment groups) developed hypothermia by 4 hours. The overall largest decrease in mean body temperatures occurred 12-24 hours after dosing. Hypothermia lasted 1-3 days in the 2.6 mg/kg group, and up to 4 days in the 5.2 and 7.8 mg/kg groups. Temperatures as low as 89, 84.2, and 92.1°F in the 2.6, 5.2, and 7.8 mg/kg groups, respectively, were recorded.

Other adverse reactions in all treated groups were salivation, vomiting, and mydriasis. Fecal abnormalities included blood in the feces, diarrhea, and lack of feces. Blood in the feces increased in severity with increased dose and repeated doses. In the 2.6 mg/kg group, 2 dogs had blood in the feces once after the first or second dose; a third 2.6 mg/kg dog had 4 observations after the second dose and 10 observations after the third dose.

Daily food consumption and body weight decreased after fentanyl dosing, especially in the higher dose groups. In the 2.6 mg/kg group, food consumption decreased 87% after the first dose, then 70% and 37% after doses 2 and 3, returning to pre-treatment food consumption by day 12. Dogs lost the most body weight in the first dose period. In the 2.6 mg/kg group, three dogs lost 19-20% and three dogs lost 5-10% body weight. All dogs in the 5.2 and 7.8 mg/kg groups lost between 10-21% body weight.

Increases in mean hematocrit, hemoglobin, red blood cell count, albumin, globulin, and total protein values were consistent with dehydration and most pronounced in the 2 higher dose groups. These values were highest on day 4, dropping below day 0 mean values by the end of the study. Three of 8 dogs in the 2.6 mg/kg group had reticulocyte decreases of approximately 85% at day 12 compared to day 0 with markedly lower values in the 5.2 and 7.8 mg/kg groups by days 8 and 12. Other clinically relevant clinical pathology changes included above normal WBC counts (3 dogs in the 7.8 mg/kg group), above normal APTT values in 2 dogs in each of the higher dose groups, and dose related increases in fibrinogen values in all 3 groups, peaking at day 4 and decreasing thereafter.

Necropsy findings included multifocal intestinal ulceration (moderate necrosis) in 1 dog (5.2 mg/kg), multifocal intestinal erosions in 1 dog (5.2 mg/kg), and mucosal congestion (with red or black intestinal contents) in 2 dogs. All 3 dogs that died had diffuse proteinaceous casts in the renal tubules. Bone marrow evaluation (not performed in the 3 dogs that died) showed changes consistent with an increased demand for white blood cells, including dogs in the 2.6 mg/kg group.

STORAGE INFORMATION

Store at controlled room temperature, 20 - 25°C (68 - 77°F). Once broached with the needleless adaptor, store the vial upright at controlled room temperature, 20 - 25°C (68 - 77°F), with the needleless adaptor attached. Discard broached vials after 30 days.

REFERENCES

1Mills CA, et al. J Anesth. Narcotic reversal in hypercapnic dogs: comparison of naloxone and nalbuphine. 1990, 37(2): 238-244.

2Plumb DC. In: Plumb’s Veterinary Drug Handbook, 5th edition. Ames: Blackwell Publishing, 2005;547.

3Mealey KL, Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Therap. 2004, 27:257-264.

4Mealey KL, Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001, 11:727-733.

5Otsuka H, et al. Pharmacokinetics of fentanyl after intravenous and subcutaneous administration to rats and dogs. Jpn Pharmacol Ther. 2001, 29(11):877-886.

6Lu PL, et al. Selective Inhibition of Dog Hepatic CYP2B11 and CYP3A12 J Pharmacol Exp Ther. 2005, 313(2):518-528. 7Thompson SJ, et al. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology. 2000 May; 92(5):1392-1399.

HOW SUPPLIED

RECUVYRA is supplied in 10 mL amber-colored glass vials (50 mg fentanyl/mL). Each vial is supplied with a purpose-designed needleless adaptor, syringes and applicator tips.

NADA 141-337, Approved by FDA NDC 0986-4232-11

Manufactured for Elanco Animal Health, A Division of Eli Lilly and Company, Indianapolis, IN 46285

CA4232

PA088024AMA (Aug 2014)

Elanco, Recuvyra and the diagonal bar are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates.

NAC No.: 1031056.1

ELANCO ANIMAL HEALTH
A Division of Eli Lilly & Co.

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Website:   www.elanco.com
Email:   elanco@elanco.com
Every effort has been made to ensure the accuracy of the Recuvyra 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 © 2016 North American Compendiums. Updated: 2016-08-21

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