Ruconest

Conestat alfa is a manmade form of a protein called C1 esterase inhibitor that occurs naturally in the bloodstream and helps control swelling in the body. People with a condition called hereditary angioedema do not have enough of this protein. Hereditary angioedema can cause attacks of swelling and symptoms such as stomach problems or trouble breathing.

Conestat alfa is used to treat angioedema attacks in people with hereditary angioedema. Conestat alfa is for use in adults and children who are at least 13 years old.

Conestat alfa may also be used for purposes not listed in this medication guide.

You should not use this medicine if you are allergic to rabbits or rabbit products (meat, fur, pelt).

You should not use conestat alfa if you are allergic to it, or:

• if you are allergic to rabbits or rabbit products (meat, fur, pelt); or
• if you have ever had a life-threatening allergic reaction to conestat alfa or to another C1 esterase inhibitor (such as Berinert or Cinryze).

To make sure conestat alfa is safe for you, tell your doctor if you have:

• coronary artery disease (hardened arteries); or
• a history of stroke or blood clot.

This medicine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

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

Conestat alfa is not approved for use by anyone younger than 13 years old.

Allergic reactions may occur. Get medical treatment immediately if you have any of the following symptoms after receiving this medication:

• wheezing
• difficulty breathing
• chest tightness
• turning blue (look at lips and gums)
• fast heartbeat
• swelling
• faintness
• rash
• hives

In clinical studies, the most severe side effect reported in a person who received this medication was a severe allergic reaction in a subject who was allergic to rabbits.

Other side effects patients experienced during clinical research studies include:

• headache
• nausea
• diarrhea

These are not all the possible side effects of Ruconest. Ask your doctor or pharmacist for more information.

Call your doctor for advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

No drug interactions have been reported. Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines such as over-the-counter medicines, supplements, or herbal remedies.

The first treatment is typically under the supervision of a qualified healthcare professional experienced in the treatment of HAE.

Appropriately trained patients may self-administer upon recognition of an HAE attack.

The recommended dose of Ruconest is 50 IU per kg with a maximum of 4200 IU to be administered as a slow intravenous injection over approximately 5 minutes.

If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 hour period.

Ruconest is usually administered by a healthcare provider in a medical setting making it unlikely for an overdose to occur. However, if overdose is suspected, seek emergency medical attention.

You should not use conestat alfa if you are allergic to it, or:

• if you are allergic to rabbits or rabbit products (meat, fur, pelt); or

• if you have ever had a life-threatening allergic reaction to conestat alfa or to another C1 esterase inhibitor (such as Berinert or Cinryze).

To make sure conestat alfa is safe for you, tell your doctor if you have:

• coronary artery disease (hardened arteries); or

• a history of stroke or blood clot.

This medicine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

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

Conestat alfa is not approved for use by anyone younger than 13 years old.

Since conestat alfa is used when needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using this medicine.

• Serine protease inhibitor that principally regulates the activation of the complement and intrinsic coagulation (e.g., contact system) pathways.1 2 6 7 8 10 12 19 22 23 31 34 Also plays a role in the fibrinolytic system.2 6 10 12 14 19 31 34

• Regulates contact system activation by inhibiting plasma kallikrein and coagulation factor XIIa; such actions prevent formation of bradykinin, the presumed mediator of increased vascular permeability in HAE.1 2 6 7 8 9 10 12 13 32 33

• Blocks both the spontaneous activation of C1 complement and formation of activated C1 complement, suppressing the classical complement pathway.1 6 7 12

• Also exhibits inhibitory effects on plasmin.8 12 23

• Binds to and forms irreversible complexes with target protease, which are then inactivated and removed from circulation.1 6 7 9 22 32

• Biosynthetic (recombinant DNA origin) preparation of human C1-esterase inhibitor produced from the milk of transgenic (genetically modified) rabbits.1 37 Undergoes a series of viral reduction steps (e.g., pasteurization, precipitation, nanofiltration, chromatography) to reduce risk of viral transmission.1 8 15 37

• Structurally and functionally similar to plasma-derived C1-esterase inhibitor.1 8 32

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the effects of Ruconest on carcinogenesis and mutagenesis. Fertility was not evaluated in animal studies.

Animal Toxicology and/or Pharmacology

Single- and repeat-dose studies of up to 14 days in rats, dogs, and cynomolgus monkeys with daily doses of Ruconest up to 80 times the human dose (50 U/kg) were conducted. In a 14-day monkey toxicology study of intravenous doses up to 2000 U/kg twice daily, increases in AST and ALP were observed at doses of 500 U/kg and higher. No histopathological correlates were observed in the liver and the increases in liver enzymes were reversible. Histologic findings included changes in the size of thymic cortex and medulla, and microvacuoles in the epithelial cells lining the renal tubules. The renal tubular vacuolation was dose dependent, but was not accompanied by other histological changes in the kidney. This finding was only partially reversible at the highest dose level of 2000 U/kg twice daily. It was concluded that the NOAEL of Ruconest was 1000 U/kg twice daily in this species. There were no adverse findings in a safety pharmacology study in dogs and a local tolerance study in rabbits. It is concluded that preclinical toxicology data for daily doses up to 40 times the proposed human dose of Ruconest (50 U/kg) do not indicate a safety concern for the use of Ruconest in humans.

Embryo-fetal studies have been conducted in rabbits and rats at a dose of Ruconest 12.5 times the human dose of 50 U/kg. In rats, no malformed fetuses were observed. In rabbits, an increase in the incidence of fetal cardiac vessel defects was observed (1.12% [2 cases] in the treatment group compared to 0.03% in historical controls). These defects are considered to be a chance finding, but a Ruconest-related effect cannot be excluded.

Applies to conestat alfa: intravenous solution reconstituted