RUCONEST is a C1 esterase inhibitor [recombinant] indicated for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE).

Limitation of Use: Effectiveness was not established in HAE patients with laryngeal attacks.

For intravenous use after reconstitution only.

• RUCONEST is available as a lyophilized powder for reconstitution for injection in a single-use 25 mL glass vial. Each vial contains 2100 U of rhC1INH.

• RUCONEST is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products.
• RUCONEST is contraindicated in patients with a history of life-threatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis.

The serious adverse reaction in clinical studies of RUCONEST was anaphylaxis.

The most common adverse reactions (≥ 2%) reported in all clinical trials were headache, nausea, and diarrhea.

RUCONEST is a recombinant analogue of human complement component 1 esterase inhibitor for intravenous injection. RUCONEST is purified from the milk of transgenic rabbits, and supplied as a sterile, preservative-free, white/off-white lyophilized powder for reconstitution for injection. One U of rhC1INH activity is defined as the equivalent of C1 esterase inhibiting activity present in 1 mL of pooled normal plasma.

RUCONEST is a soluble, single-chain glycoprotein containing 478 amino acids, with a molecular mass of 68 kDa, of which approximately 22% comprises oligosaccharide structures. The primary and secondary structures of the molecule and target protease selectivity are consistent with those of plasma-derived C1 esterase inhibitor.

Each vial of RUCONEST contains 2100 U of rhC1INH, 937 mg of sucrose, 83.3 mg of sodium citrate dihydrate and 1.0 mg of citric acid monohydrate. After reconstitution with 14 mL of sterile Water for Injection, each vial of RUCONEST contains 150 U of rhC1INH per 1 mL in a 20 mM sodium citrate buffer with a pH of 6.8. RUCONEST does not contain preservatives and each vial is for single use only.

RUCONEST is purified from the milk of transgenic rabbits. The rabbits are maintained in a closed colony that is controlled and routinely monitored for specific pathogens. The skimmed milk is screened for adventitious contaminants prior to further manufacture. The manufacturing process has been validated to demonstrate adequate capacity for removal and/or inactivation of viruses ( Table 4). RUCONEST contains less than 0.002% of host-related impurities.

The safety and efficacy of RUCONEST for treatment of acute angioedema attacks in patients with HAE was established in Study 1, a double-blind, randomized, placebo-controlled trial (RCT) which included an open-label extension (OLE) phase; and supported by the results of 2 additional RCTs and 2 additional OLE studies.

Randomized, Controlled Trials

The safety and efficacy of RUCONEST in the treatment of acute attacks in patients with hereditary angioedema were demonstrated in a placebo-controlled, double-blind, randomized study (Study 1). Supportive evidence of effectiveness is provided by two double-blind, randomized, placebo-controlled studies (Studies 2 and 3). Evidence for the efficacy of repeat treatment of HAE attacks is provided from the open-label extensions (OLE) of each of the three randomized studies.

Study 1 was a randomized, double-blind, placebo-controlled trial that included an open-label extension (OLE) phase to assess the efficacy and safety of RUCONEST 50 U/kg in the treatment of acute attacks in patients with HAE. Seventy-five (75) adults and adolescent patients were randomized (3:2) to receive RUCONEST 50 U/kg (N = 44) or placebo (N = 31). Patients ranged in age from 17 to 69 years of age; 63% were female and 37% were male; 96% were Caucasian.

The primary efficacy endpoint was the time to beginning of relief of symptoms, assessed using patient-reported responses to two questions from a Treatment Effect Questionnaire (TEQ). The TEQ required patients to assess the severity of their attack symptoms at each affected anatomic location, using a seven-point scale (“much worse” to “much better” [TEQ Question 1]), and whether their symptoms had begun to decrease notably since receiving the study medication (“yes” or “no” [TEQ Question 2]). To achieve the primary endpoint, a patient had to have a positive response to both questions along with persistence of improvement at the next assessment time (i.e., the same or better response).

Rescue treatment with RUCONEST was available for patients who did not experience the beginning of relief at 4 hours after study drug administration, or earlier to patients who experienced life-threatening oropharyngeal-laryngeal angioedema symptoms. If a patient received a medication which could have impacted the efficacy evaluation or open-label RUCONEST as rescue medication, prior to achieving beginning of relief of symptoms, the time to beginning of relief of symptoms was censored at the last assessed time prior to medication use.

In the RCT phase, the median time to beginning of relief of symptoms was statistically significantly shorter in patients treated with RUCONEST 50 U/kg compared with patients treated with placebo as assessed by the TEQ; ( Table 6, Figure 1).

Figure 1. Kaplan-Meier Plot of Time to Beginning of Relief of Symptoms (Study 1, RCT Phase)

Among several planned subgroup analyses, descriptive statistics showed that in US patients a median time to beginning of relief of symptoms with persistence at the primary attack location (based on TEQ) was 98 minutes [95% CI:(45, 240); n=22] for those receiving RUCONEST and 90 minutes [95% CI: (50, -); n=16] for those receiving placebo. The hazard ratio for time to the beginning of relief of symptoms in this subpopulation was 1.20 [95% CI: 0.48 to 3.01] for patient receiving RUCONEST as compared with patient receiving placebo. Non-US patients receiving RUCONEST had a median time to beginning of relief of 90 minutes [95% CI: (63, 120); n=22] and non-US patients receiving placebo had a median time to beginning of relief of 334 minutes [95% CI: (150, -); n=15]. The hazard ratio for the non-US subgroup was 4.82 [95% CI: 1.58 to 14.72] for patients receiving RUCONEST compared to placebo.

Examination of gender subgroups suggested a larger treatment effect in men than women. For women receiving RUCONEST, the median time to beginning of relief was 113 minutes [95% CI: (63, 151); n=28], and for women receiving placebo, the median time to beginning of relief was 105 minutes [95% CI: (60, 334); n=19]. The hazard ratio for women receiving RUCONEST versus placebo was 1.22 [95% CI: 0.60 to 2.48]. For men receiving RUCONEST, the median time to beginning of relief was 75 minutes [95% CI: (45, 210); n=16], and for men receiving placebo, the median time to beginning of relief was 480 minutes [95% CI: (150, -) n=12]. The hazard ratio for men receiving RUCONEST versus placebo was 3.94 [95% CI: 1.23 to 12.68].

No plausible biological explanations for the regional or gender subgroup effects were found. One possible explanation is a larger-than-expected placebo response among US women. None of the subgroup confidence intervals were adjusted for multiplicity.

Because almost all of the patients were Caucasian and were between 18 and 65 years of age, race and age subgroup analyses were not considered meaningful.

Among patients who achieved relief within 4 hours, there were 4 (27%) patients in the placebo group who had a relapse of their symptoms within 24 hours as compared with 1 (3%) in the RUCONEST group. The proportion of patients who received RUCONEST as rescue medication was greater in patients randomized to placebo (13 of 31 patients; 42%) than in patients randomized to RUCONEST (5 of 44 patients; 11%).

The efficacy of RUCONEST 50 U/kg for different anatomical locations of HAE attacks is summarized in Table 7.

In the OLE phase of Study 1, patients were treated with open-label RUCONEST 50 U/kg for repeated attacks of HAE. Forty-four patients who completed the RCT phase were enrolled into the OLE phase where they were treated for a total of 170 attacks. In this phase, the median time to beginning of relief of symptoms was 75 minutes (95% CI: 64, 90), consistent with the results of the RCT phase of the study ( Table 6). Results were also comparable across attacks, suggesting that the efficacy of RUCONEST 50 U/kg was maintained over repeated attacks of HAE. In the OLE phase of Study 1, 5/170 (3%) attacks received a second dose of RUCONEST 50 U/kg.

In Study 2 (North American RCT), patients were randomized to receive a single administration of either RUCONEST 50 U/kg (N=12), RUCONEST 100 U/kg (N=13) or placebo (N=13). Patients ranged in age from 17 to 66 years of age; 74% were female and 26% were male; and 92% were Caucasian.

In Study 3 (European RCT), patients were randomized to receive a single administration of either RUCONEST 100 U/kg (N=16) or placebo (N=16). Patients ranged in age from 17 to 71 years of age: 53% were female and 47% were male; and 100% were Caucasian.

Patients scored their symptoms using a visual analog scale (VAS) ranging from 0-100 mm. A VAS decrease of > 20 mm compared with baseline with persistence of the improvement at two consecutive time points was considered the onset of relief in Studies 2 and 3.

In both Study 2 and 3, the efficacy of RUCONEST in the treatment of acute angioedema attacks was demonstrated by significantly shorter times to beginning of relief of symptoms based on the VAS (Figure 2).

Figure 2. Mean VAS scores over time with 95% Confidence Intervals (Study 2 and 3, RCT Phase)

In open-label extension studies of Study 2 and 3, 119 patients were treated with RUCONEST for a total of 362 acute angioedema attacks. As observed in Study 1, the efficacy of RUCONEST was maintained for repeat attacks.

1. Sulikowski T, Patston PA. The inhibition of TNK-t-PA by C1-inhibitor. Blood Coagul Fibrinolysis. 2001 Jan;12(1):75-7.
2. Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation. 1997 Aug 5;96(3):761-8.
3. Huisman LG, van Griensven JM, Kluft C. On the role of C1-inhibitor as inhibitor of tissue-type plasminogen activator in human plasma. Thromb Haemost. 1995 Mar;73(3):466-71.
4. Gurewich V, Pannell R. Recombinant human C1-inhibitor prevents non-specific proteolysis by mutant pro-urokinase during optimal fibrinolysis. Thromb Haemost. 2009 Aug;102(2):279-86.
5. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE. C1-esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev. 2000 Mar;52(1):91-112.
6. German Medical Profession’s Drugs Committee [Arzneimittelkommission der deutschen Arzteschaft]. Severe thrombus formation of Berinert ® HS [Schwerwiegende Thrombenbildung nach Berinert ® HS]. Deutsches Ärzteblatt. 2000 April 2000; 97(Heft 15): A-1016.
7. Horstick, G, Berg O, Heimann A, Gotze O, Loos M, Hafner G, et al. Application of C1-esterase inhibitor during reperfusion of ischemic myocardium: dose-related beneficial versus detrimental effects. Circulation. 2001 Dec 18;104(25):3125-31.

Advise the patient to read the FDA-Approved patient labeling (Product Information and Instructions for Use).

Patients being treated with RUCONEST should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of RUCONEST.

• Advise female patients to notify their physician if they are pregnant or intend to become pregnant during the treatment of acute attacks of HAE with RUCONEST.

• Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.

• Inform patients of the risks and benefits of RUCONEST before prescribing or administering it to the patient.

Advise patients to immediately report :

• Signs and symptoms of allergic hypersensitivity reactions, such as hives, urticaria, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of RUCONEST ( see WARNINGS AND PRECAUTIONS/Hypersensitivity [ 5] ).

Manufactured by:

Pharming Americas B.V.

Darwinweg 24

2333 CR Leiden

The Netherlands



RUCONEST ® is a registered trademark of Pharming Intellectual Property B.V.

Distributed by:

Pharming Healthcare Inc.

Bridgewater

NJ 08807

Product protected by U.S patent Nos. 7,067,713 and RE43691.

Please see www.ruconest.com for patent information.

US License No. 2079

REV NOV 2017

RUCONEST ® (ROO-Ko-nest)

( C1 esterase inhibitor [recombinant])

Lyophilized powder for reconstitution for injection in a single-use vial

This leaflet summarizes important information about RUCONEST. Please read it carefully each time before using RUCONEST. There may be new information provided. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about RUCONEST. If you have any questions after reading this, ask your healthcare provider.

What is RUCONEST?

RUCONEST is an injectable medicine that is used to treat acute angioedema attacks in adult and adolescent patients with Hereditary Angioedema (HAE). HAE is caused by a shortage of a protein called C1 esterase inhibitor, that is present in your blood and helps control inflammation (swelling) and parts of the immune system. A shortage of C1 esterase inhibitor can lead to repeated attacks of swelling, pain in the abdomen, difficulty breathing and other symptoms. RUCONEST contains C1 esterase inhibitor.

Who should not use RUCONEST?

You should not use RUCONEST if you have a known or suspected allergy (hypersensitivity) to rabbits or rabbit-derived products.

You should not use RUCONEST if you have experienced life-threatening immediate hypersensitivity reactions, including anaphylaxis, to RUCONEST or to any other C1 esterase inhibitor product.

RUCONEST is not indicated for use in children under the age of 13 years.

What should I tell my healthcare provider before using RUCONEST?

Tell your healthcare provider about all of your medical conditions, including if you:

• have an allergy to rabbits since this can put you at high risk of a serious allergic reaction with RUCONEST. These allergy symptoms could include runny nose, itchy nose, sneezing, coughing, wheezing, difficulty breathing or watery eyes when you are near rabbits.
• are pregnant or planning to become pregnant. It is not known if RUCONEST can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if RUCONEST passes to your milk and if it can harm your baby.

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.

How is RUCONEST given?

RUCONEST will be slowly injected into your vein (intravenous injection). Before injection, the RUCONEST powder must be dissolved using sterile Water for Injection. The dose will be determined based on your weight.

Most of the time a single dose of RUCONEST is enough to treat an attack, but a second dose may be needed.

What are the possible side effects of RUCONEST?

Like all medicines, RUCONEST can cause side effects, although not everybody gets them.

Allergic reactions may occur with RUCONEST. Call your healthcare provider or the emergency department immediately if you have any of the following symptoms after receiving RUCONEST:

• 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 RUCONEST 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.

If any of the side effects get serious, or if you notice any side effects not listed in the leaflet, please inform your healthcare provider or pharmacist. You can also report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or contact Pharming Healthcare Inc. at 1-800-930-5221.

You can ask your healthcare provider for information about RUCONEST that is written for healthcare providers.

General Information about RUCONEST

Do not use RUCONEST for a condition for which it is not prescribed.

If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about RUCONEST that was written for healthcare professionals.

For more information go to www.ruconest.com or call 1-800-930-5221.

RECOMMENDED PREPARATION OF MEDICATION AND MATERIALS
Use aseptic (sterile) technique when preparing and administering RUCONEST.
Step 1: Assemble supplies from medication box on a clean flat surface. 2 single-use vials of RUCONEST Sterile Water for Injection (diluent), 14mL per vial of RUCONEST to be reconstituted. Antiseptic wipes 1 syringe, 30 mL Needle-free, vented or non-vented vial adapters (or large bore needle). Use a new vial adapter for each vial of RUCONEST and diluent.
Step 2: Inspect the RUCONEST vial. Do not use if: The protective cap is missing The expiration date (see label) has passed
Step 3: Wash hands. Thoroughly wash and dry your hands

DOSAGE VERIFICATION

Discuss this section with your healthcare provider to ensure that the correct dose of RUCONEST is administered.

• The dose of RUCONEST and volume (mL) of reconstituted solution to be administered is based on body weight show in the chart below. No more than 2 vials may be combined for a single dose.

RECONSTITUTION The procedures below are provided as general guidelines for the reconstitution of RUCONEST.
Step 1: Ensure that the RUCONEST vials and the diluent vial are at room temperature (range of 68°F - 77°F or 20°C - 25°C). The RUCONEST vial is for single
Step 2: Place the 2 RUCONEST vials and the diluent vial on a flat surface and remove the flip caps on each vial Wipe the vial stoppers with the antiseptic wipes provided and allow to dry for 30 seconds. Do not blow on the stoppers after wiping. Do not touch the stopper with your hands, or allow it to touch any surface.
Step 3: Peel back the covers from the clear plastic vial adapter packages. Leave the adapters in their packages.
Step 4: While holding the adapter in its package, place the first adapter over the diluent vial and press down until the device snaps into place. Leave the package on the adapter until you are ready to attach the syringe.
Step 5: Now, place a 2nd adapter over a RUCONEST vial and press down until it snaps into place. Repeat if your dose requires a 2nd RUCONEST vial.
Step 6: Lift the package away from the diluent adapter.
Step 7: Remove syringe from package and withdraw sterile water for injection from the diluent vial. With vial on a flat surface, attach syringe to adapter on diluent vial by rotating syringe clockwise. Turn diluent vial upside down and slowly withdraw either 14 mL (if using 1 RUCONEST vial) or 28 mL (if using 2 RUCONEST vials) of diluent into syringe by gently pulling back on the plunger. There will still be some diluent left in the vial. Place the diluent vial back on a flat surface and detach syringe by gently pulling the syringe and rotating counterclockwise.
Step 8: Transfer the diluent to the RUCONEST vial. Remove the package from the adapter connected to one of the RUCONEST vials. Attach the syringe holding the diluent to the adapter on the RUCONEST vial by inserting the tip into the adapter opening while firmly pushing and rotating the syringe clockwise. Slowly press 14 mL of diluent into the RUCONEST vial. Add the diluent slowly to avoid forceful impact on the powder. Note: Leave the syringe attached to the vial after adding the diluent.
Step 9: Swirl the vial to mix. Do this slowly to avoid foaming. Repeat Steps 8 and 9 if you are using a second RUCONEST vial. Remove syringe from the first RUCONEST vial prior to attaching to the second vial.
Step 10: Inspect RUCONEST vial(s) visually. After reconstitution and prior to administration, inspect the RUCONEST vials visually for particulate matter and discoloration. The reconstituted solution should be colorless, clear, and free from visible particles. Do not use the vial if it looks cloudy, contains particles, or has changed color.
Step 11: With the syringe still connected to the RUCONEST vial, turn the vial upside down. Slowly withdraw your dose of RUCONEST by gently pulling back on the plunger. Once you have withdrawn your dose, turn the vial right side up and place on a flat surface. Disconnect the syringe by gently pulling and rotating counterclockwise.
Step 12: Repeat Step 11 and withdraw additional reconstituted RUCONEST from the second RUCONEST vial (if needed). Withdraw only as much as is needed based on your body weight. Disconnect the syringe, for use as described in the next section.
SELF-ADMINISTRATION (intravenous injection) Your healthcare provider will teach you how to safely administer RUCONEST. It is important that you inject RUCONEST directly into a visible vein. Do not inject into surrounding tissues or an artery. Once you learn how to self-administer, follow the instructions provided below. The reconstituted solution should be used within 8 hours and should be cooled but not be frozen.
Step 1: Assemble supplies. Gather the RUCONEST syringe, the following disposable supplies (not provided with RUCONEST), and other items: Standard butterfly catheter infusion set (IV administration set with winged adapter and needle) Sterile syringe Tourniquet Sterile gauze and tape or transparent dressing Bandage (adhesive dressing) Gloves (if recommended by your healthcare provider) Antiseptic wipe for cleaning skin Other items (not shown) Clock or stopwatch to monitor time Sharps or other disposal container Treatment diary
Step 2: Clean surface. Thoroughly clean a table or other flat surface using one or more of the antiseptic wipes.
Step 3: Prime the infusion set. As instructed by your healthcare provider: To prime (fill) the infusion tubing, connect the syringe filled with RUCONEST to the infusion set tubing and gently push on the syringe plunger to fill the tubing with RUCONEST.
Step 4: Prepare the approved IV injection site. Apply a tourniquet above the site of the infusion. Prepare the injection site by wiping the skin well with an antiseptic wipe, beginning at the center and working outward in a circular motion. Allow the site to dry.
Step 5: Start infusion. Follow the instructions provided by your healthcare provider. Take off the needle sheath. Hold both wings of the butterfly between the thumb and the index finger with the obliquely cut (slanted) opening of the butterfly needle pointing upward. Insert the butterfly needle of the infusion set into your vein (insert as flat to skin surface as possible). Use sterile gauze and tape or transparent dressing to hold the needle in place. Make sure the needle is in a vein: Gently pull back on the syringe plunger and check to see if blood is in the tubing. If there is blood present, then the needle is in a vein. If there is no blood, remove the needle and repeat this step using a new needle, new administration tubing, and a different injection site. Remove the tourniquet. Note: Inject RUCONEST slowly over approximately 5 minutes.
Step 6: Cover the injection site and clean up. After all of the RUCONEST has been infused: Withdraw the butterfly needle along the line that it was inserted. Cover the injection site with a bandage, holding pressure on the site for a few minutes. Dispose of all unused solution, empty vials, and used needles and syringe in an appropriate container used for medical waste.
POST-ADMINISTRATION The procedures below are provided as general guidelines for after the infusion of RUCONEST.
Record each injection into treatment journal. Record the lot number from the RUCONEST vial label. Enter the date and time of your injection.

This Patient Package Insert has been approved by the US Food and Drug Administration.

Manufactured by:

Pharming Americas B.V.

Darwinweg 24

2333 CR Leiden

The Netherlands

RUCONEST ® is a registered trademark of Pharming Intellectual Property B.V.

Distributed by:

Pharming Healthcare Inc.

Bridgewater

NJ 08807

Product protected by U.S. patent Nos. 7,067,713 and RE43691.

Please see www.ruconest.com for patent information.

US License No. 2079

REV NOV 2017

RUCONEST®

C1 esterase inhibitor (recombinant)

2100 U

NDC 71274-350-01

For intravenous use only.

For single patient use.

See prescribing information for directions for use.

Rx only

RUCONEST®

C1 esterase inhibitor (recombinant)

2100 U

NDC 71274-350-02

For intravenous use only.

For single patient use.

See prescribing information for directions for use.

Rx only