Ruconest: Package Insert and Label Information

RUCONEST- conestat alfa injection, powder, for solution
Pharming Healthcare Inc.

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only.

2.1 Recommended Dosing

  • Training on how to administer RUCONEST should be conducted by 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 U per kg with a maximum of 4200 U 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 U per dose. No more than two doses should be administered within a 24-hour period.

Table 1. Recommended dose of RUCONEST for an acute attack

Body Weight

RUCONEST Dose for Intravenous Injection

Volume (mL) of Reconstituted Solution (150 U/mL) to be Administered

< 84 kg

50 U per kg

Body weight in kg divided by 3

≥ 84 kg

4200 U (2 vials)

28 mL

2.2 Preparation and Handling

  • Store RUCONEST in the original carton and protect from light prior to reconstitution.
  • Do not use after expiration date on the product vial label.
  • Water for Injection is not included in the RUCONEST package.
  • Use aseptic technique to reconstitute, mix the solution, and to combine the reconstituted solution from more than one vial ( see Reconstitution [ 2.3] and Administration [ 2.4]).
  • Do not mix or administer RUCONEST with other medicinal products or solutions.
  • Discard all partially used vials after treatment.

2.3 Reconstitution

Each package contains one single-use vial of RUCONEST. To reconstitute, the following are also required:

  • Sterile Water for Injection (diluent) — At least 14 mL per vial of RUCONEST requiring reconstitution.
  • Antiseptic wipe
  • Syringe
  • Commercially available vial adapter and syringe luer lock or large bore needle. If using a syringe with vial adapter, use a new vial adapter for each vial of RUCONEST and diluent.

The procedures below are provided as general guidelines for the reconstitution and administration of RUCONEST.

  • Ensure that the RUCONEST vial and diluent vial are at room temperature.
  • Remove the flip caps from the RUCONEST and diluent vials. Treat the vial stoppers with the antiseptic wipe and allow to dry.
  • Using the syringe/needle or syringe/vial adapter, withdraw 14 mL of sterile water for injection from the diluent vial.
  • Remove the syringe and transfer the diluent to the RUCONEST vial. Add the diluent slowly to avoid forceful impact on the powder. Swirl the vial slowly to mix and avoid foaming.
  • Repeat this procedure using another 14 mL of diluent and a second vial of RUCONEST.
  • If the same patient is to receive more than one vial, the contents of multiple vials may be pooled into a single administration device (i.e., syringe).
  • Inspect RUCONEST visually for particulate matter and discoloration after reconstitution and prior to administration. The reconstituted solution should be colorless, clear, and free from visible particles. Do not use if the solution is cloudy, colored, or contains particulates.
  • RUCONEST vial is for single-use only.
  • Use the reconstituted product immediately, or within 8 hours stored at 36ºF — 46ºF (2º — 8ºC). Discard partially used vials.
  • Do not freeze the reconstituted solution.

2.4 Administration

  • Do not mix RUCONEST with other medicinal products. Administer RUCONEST by a separate infusion line.
  • Use aseptic technique when administering RUCONEST.
  • Follow recommended venipuncture guidelines for initiating intravenous therapy.
  • Administer RUCONEST by slow intravenous injection over approximately 5 minutes.
  • For self-administration, provide the patient with instructions and training for intravenous injection outside of a clinic setting so patients may self-administer RUCONEST upon recognition of symptoms of an HAE attack [see Patient Counseling Information ( 17)].
  • After administration, immediately discard any unused product and all used disposable supplies in accordance with local requirements.

3 DOSAGE FORMS AND STRENGTHS

  • 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.

4 CONTRAINDICATIONS

  • 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.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur . The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of RUCONEST. Should symptoms occur, discontinue RUCONEST and institute appropriate treatment. Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered. [see Patient Counseling Information (17) ]

5.2 Thromboembolic Events

Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Monitor patients with known risk factors for TE events during and after RUCONEST administration.

6 ADVERSE REACTIONS

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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.

The RUCONEST clinical development program evaluated a combined total of 940 administrations in 236 subjects (symptomatic and non-symptomatic). In clinical studies, a total of 205 symptomatic HAE patients received treatment with RUCONEST for a combined total of 650 acute angioedema attacks. Among these HAE patients, 83 were treated for a single HAE attack and 122 were treated for multiple attacks.

Three randomized, placebo-controlled clinical trials (RCTs) were conducted in which 137 patients experiencing acute HAE attacks received RUCONEST (either an initial 50 U/kg or 100 U/kg body weight dose) or placebo (saline solution).

Table 2 shows all adverse reactions (ARs) in the RCTs, compared with the placebo group.

Table 2. Adverse reactions occurring In ≥ 2% of subjects in the three RCT studies

MedDRA Preferred Term

RUCONEST

100 U/kg

(N=29)

n (%)

RUCONEST

50 U/kg* (N=66) n (%)

Placebo**

(N=47) n (%)

Total number of patients with adverse reactions 4 (14%) 6 (9%) 13 (28%)
Headache 3 (10%) 0 2 (4%)
Sneezing 0 1 (2%) 0
Angioedema 1 (3%) 0 0
Erythema marginatum 0 1 (2%) 0
Skin burning sensation 0 1 (2%) 0
Back pain 0 2 (3%) 0
C-reactive protein increased 0 1 (2%) 0
Fibrin D-dimer increased 0 1 (2%) 0
Vertigo 1 (3%) 0 0
Procedural headache 0 1 (2%) 0
Lipoma 0 1 (2%) 0

* Includes 5 patients who received an additional 50 U/kg dose
MedDRA: Medical Dictionary for Regulatory Activities, version 15.0.
** Events only occurring in placebo patients are not listed.
Integrated RCT and Open-Label Extension (OLE) Studies
In a total of seven RCT and OLE studies, 205 patients experiencing acute HAE attacks were treated with RUCONEST for a total of 650 HAE attacks. Included in this population were 124 patients who were treated at the 50 U/kg dosage strength for one or more attacks.

Table 3 shows adverse reactions in ≥ 2% of patients in any RUCONEST group for the integrated dataset combining all seven RCT and OLE studies in patients experiencing acute HAE attacks.

Table 3. Adverse reactions in the seven RCT and OLE studies occurring ≥ 2% of RUCONEST-treated patients (all doses), irrespective of causality

MedDRA Preferred Term All RUCONEST doses* N=205 n (%)
Headache 19 (9%)
Nausea 5 (2%)
Diarrhea 5 (2%)

* RUCONEST doses: doses up to 100 U/kg

MedDRA: Medical Dictionary for Regulatory Activities, version 15.0.


Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Pre- and post-exposure samples from 205 HAE patients treated for 650 acute attacks with RUCONEST were tested for the antibodies against plasma-derived C1INH or rhC1INH and for antibodies against host-related impurities (HRI). Testing was performed prior to and after treatment of a first attack and subsequent repeated attacks at 7, 22 or 28, and 90 days after RUCONEST treatment.

Prior to the first exposure to RUCONEST, the frequency of anti-C1INH antibodies varied from 1.2% to 1.6% of samples. After the first exposure, the frequency of anti-C1INH antibodies varied from 0.6% to 1.0% of samples tested. After repeated exposures, the frequency of anti-C1INH antibodies varied from 0.5 to 2.2% of samples tested. The frequency of anti-HRI antibodies was 1.0% in pre-exposure samples, and after the first exposure varied from 3.5% to 4.6%. After repeated exposure, the frequency of anti-HRI antibodies varied from 5.7% to 17% of samples. At least 10% of subjects formed a specific antibody response to RUCONEST after five treated HAE attacks. No anti-C1INH neutralizing antibodies were detected. Observed anti-C1INH and anti-HRI antibodies were not associated with adverse clinical findings.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RUCONEST with the incidence of antibodies to other products may be misleading.


Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Adverse reactions in HAE patients receiving RUCONEST include abdominal pain and rash.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of RUCONEST in pregnant women. In the U.S. general population, regardless of drug exposure, available data suggest that major birth defects occur in 2 to 4% of the general population and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

Data

Human Data

Limited available postmarketing safety data with RUCONEST use in pregnant women do not indicate any adverse effects in this population. In a retrospective case collection study, 14 pregnant women aged 17 to 37 years with HAE received RUCONEST at 50 U/kg (max 4200 U) via intravenous administration for treatment of acute atttacks or for prophylaxis during pregnancy. For all 14 women in this study, delivery at full term with the births of healthy babies occurred without complications. No adverse events related to RUCONEST treatment were reported during the pregnancy period. 1,2 However these data cannot definitely establish the absence of any risk because of the small sample size and non-randomized study design.

Animal Data

Embryo toxicity with 625 U/kg of RUCONEST (12.5 times the human dose) was tested after intravenous dosing of pregnant rats in a segment II (embryofetal toxicity) study design. There were no significant outcomes from this study. Dosing of pregnant rabbits with 625 U/kg during organogenesis showed no drug-related adverse effects on either the developing fetuses or mothers [see Animal Toxicology and/or Pharmacology (13.2)].

8.2 Lactation

Risk Summary

There are no data on the presence of RUCONEST in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RUCONEST and any potential adverse effects on the breastfed child from RUCONEST or from the underlying maternal condition.

8.4 Pediatric Use

The safety and efficacy of RUCONEST were evaluated in 17 adolescent patients (13-17 years of age) treated for 52 HAE attacks. Eight out of 17 (47%) adolescent patients experienced adverse reactions. No serious adverse reactions were reported in these patients. The most common reactions (occurring in at least 2 patients) were: abdominal pain, headache, and oropharyngeal pain.

8.5 Geriatric Use

The clinical studies of RUCONEST included seven patients older than 65 years. The clinical studies included an insufficient number of patients in this age group to determine if they respond differently from younger patients.

11 DESCRIPTION

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.

Table 4. Viral reduction capacity of the rhC1INH manufacturing process
a MLV: Murine leukemia virus; REO-3: Reovirus type 3; ORF: Scab-mouth ORF virus; FCV: Feline calicivirus; PPV: Porcine parvovirus; b SP BB: SP Sepharose BB; SD: Solvent/detergent; Q HP: Q Sepharose HP; Zn FF: Zinc Chelating Sepharose FF; c Not added to the total reduction factor since independence of clearance mechanism has not been experimentally verified; d Not applicable since indicated model virus is not enveloped; e Not tested because SD chemicals are present in the starting material.

Virus Reduction Factor (Log 10 )

Step

MLV a

REO 3

ORF

FCV

PPV

SP BB chromatography b

1.8

2.2 c

1.5 c

2.3

1.5 b

SD incubation b

≥ 5.8

NA d

3.7

NA

NA

Q HP chromatography b

NT e

4.8

NT

0.8 c

2.2

Zn FF chromatography b

1.1 c

3.2 c

3.3

1.9 c

0.4 c

Nanofiltration

≥ 5.5

≥ 6.5

≥ 5.8

≥ 6.9

5.8

Total reduction factor

≥ 13.1

≥ 11.3

≥ 12.8

≥ 9.2

8.0

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