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RUCONEST
(C1 esterase inhibitor [recombinant]) for Intravenous Injection
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 IU 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 IU 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 IU 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
| Step | Virus Reduction Factor (Logio) | ||||
| MLVa | REO 3 | ORF | FCV | PPV | |
| SP BB chromatographyb | 1.8 | 2.2 c | 1.5 c | 2.3 | 1.5 b |
| SD incubationb | ≥ 5.8 | NAd | 3.7 | NA | NA |
| Q HP chromatographyb | NT e | 4.8 | NT | 0.8 c | 2.2 |
| Zn FF chromatographyb | 1.1c | 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 |
| 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. |
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RUCONEST is a C1 esterase inhibitor [recombinant] indicated for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE).
Effectiveness was not established in HAE patients with laryngeal attacks.
For intravenous use after reconstitution only.
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.
Table 1: Recommended dose of RUCONEST for an acute attack
| Body Weight | RUCONEST Dose for Intravenous Injection | Volume (mL) of Reconstituted Solution (150 IU/mL) to be Administered |
| < 84 kg | 50 IU per kg | Body weight in kg divided by 3 |
| ≥ 84 kg | 4200 IU (2 vials) | 28 mL |
Each package contains one single-use vial of RUCONEST. To reconstitute, the following are also required:
The procedures below are provided as general guidelines for the reconstitution and administration of RUCONEST.
Manufactured by: Pharming Technologies B.V., Darwinweg 24, NL-2333 CR Leiden. Distributed by: Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Inc., Raleigh, NC 27615. Revised: Feb 2015
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.
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 nonsymptomatic). 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 IU/kg or 100 IU/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 IU/kg (N=29) n (%) |
RUCONEST 50IU/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 IU/kg
dose MedDRA: Medical Dictionary for Regulatory Activities, version 15.0. ** Events only occurring in placebo patients are not listed |
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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 IU/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 IU/kg MedDRA: Medical Dictionary for Regulatory Activities, version 15.0. |
|
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% to1.0% 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.
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.
No information provided.
Included as part of the PRECAUTIONS section.
Severe hypersensitivity reactions may occur [see PATIENT INFORMATION]. 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.
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.
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 patients to immediately report:
No animal studies have been conducted to evaluate the effects of RUCONEST on carcinogenesis and mutagenesis. Fertility was not evaluated in animal studies.
Studies performed in rats and rabbits at doses up to 12.5 times the human dose of 50 IU/kg could not exclude an effect on embryofetal development. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, RUCONEST should only be used during pregnancy if clearly needed.
The safety and efficacy of RUCONEST administration prior to or during labor and delivery have not been established. Use only if clearly needed.
It is not known if RUCONEST is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RUCONEST is administered to a nursing woman.
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.
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.
No information provided.
C1 esterase inhibitor (C1INH) is a normal constituent of human blood and is one of the serine protease inhibitors (serpins). The primary function of C1INH is to regulate the activation of the complement and contact system pathways. Regulation of these systems is performed through the formation of complexes between the protease and the inhibitor, resulting in inactivation of both and consumption of the C1INH.
C1INH exerts its inhibitory effect by irreversibly binding several proteases (target proteases) of the contact and complement systems. The effect of RUCONEST on the following target proteases was assessed in vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition kinetics were found to be comparable with those observed for plasma-derived human C1INH.
HAE patients have low levels of endogenous or functional C1INH. Although the events that induce attacks of angioedema in HAE patients are not well defined, it is thought that contact system activation, and resulting increased vascular permeability lead to the clinical manifestation of HAE attacks. Suppression of contact system activation by C1INH through the inactivation of plasma kallikrein and factor XIIa is thought to modulate vascular permeability by preventing the generation of bradykinin.5
Administration of RUCONEST increases plasma levels of functional C1INH activity.
The complement component (protein) C4 is a substrate for activated C1. Patients with HAE have low levels of C4 in the circulation; RUCONEST shows a dose-dependent restoration of complement homeostasis of C4 in HAE patients. A dose of 50 IU/kg of RUCONEST increases plasma C1INH activity levels to greater than 0.7 IU/mL (the lower limit of normal) in HAE patients.
The pharmacokinetics of RUCONEST was evaluated in a study of 12 asymptomatic HAE patients (dose ranged from 6.25 IU/kg to 100 IU/kg). Pharmacokinetics evaluation was performed by non-compartmental analysis, using functional C1INH levels. Following administration of RUCONEST (50 IU/kg) in asymptomatic HAE patients (Table 5), the mean Cmax was 1.2 IU/mL, and the elimination half-life was approximately 2.5 hours. The clearance of RUCONEST was nonlinear (clearance decreased with increasing dose) over the dose range of 25-100 IU/kg.
Table 5: Baseline corrected pharmacokinetic parameters
(Mean ± SD) following administration of 50 IU/kg and 100 IU/kg RUCONEST to
asymptomatic HAE patients
| Parameters | 50 IU/kg | 100 IU/kg |
| Cbaseline (IU/mL) | 0.18 ± 0.12 | 0.14 ± 0.08 |
| Cmax (IU/mL) | 1.2 ± 0.2 | 2.3 ± 0.2 |
| Tmax (hours) | 0.31 ± 0.10 | 0.31 ± 0.10 |
| AUC (IU x hr/mL) | 3.3 ± 1.0 | 10.6 ± 2.5 |
| CL (mL/hr) | 1207±414 | 781± 147 |
| Half- life (hours) | 2.4 ± 0.6 | 2.7 ± 0.3 |
| Vss (L) | 3.0 ± 0.9 | 2.4 ± 0.5 |
Studies have not been conducted to evaluate the PK of RUCONEST in special patient populations, identified by race, age (pediatric or geriatric), or the presence of renal or hepatic impairment.
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 IU/kg) were conducted. In a 14-day monkey toxicology study of intravenous doses up to 2000 IU/kg twice daily, increases in AST and ALP were observed at doses of 500 IU/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 IU/kg twice daily. It was concluded that the NOAEL of RUCONEST was 1000 IU/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 IU/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 IU/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.
The safety and efficacy of RUCONEST for treatment of acute angioedema attacks in patients with HAE was established in Study 1, a doubleblind, 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.
The safety and efficacy of RUCONEST in the treatment of acute attacks in patients with hereditary angioedema were demonstrated in a placebocontrolled, 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 IU/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 IU/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 IU/kg compared with patients treated with placebo as assessed by the TEQ; (Table , Figure 1).
Table 6: Time to Beginning of Relief of Symptoms based
on questionnaire based on TEQ (Study 1, RCT Phase)
| Time to Beginning of Relief of Symptoms, minutes | RUCONEST 50 IU/kg N=44 |
Placebo N=31 |
| Median95% CI | 90 (61, 150) | 152 (93, -) |
| Log-rank p-value | 0.031 | |
| Values that are not estimable are displayed as '- '. | ||
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 patients receiving RUCONEST as compared with patients 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 IU/kg for different anatomical locations of HAE attacks is summarized in Table 7.
Table 7: Proportion of patients who achieved relief
within 4 hours, by attack type
| Attack Type | RUCONEST 50 IU/kg n/N (%) |
Placebo n/N (%) |
| Abdominal | 14/16 (88%) | 7/12 (58%) |
| Facial | 3/6 (50%) | 0/2 (0%) |
| Peripheral (extremities) | 17/20 (85%) | 7/14 (50%) |
| *Life-threatening laryngeal attacks were excluded from the randomized-controlled phase of Study 1 | ||
In the OLE phase of Study 1, patients were treated with open-label RUCONEST 50 IU/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 IU/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 IU/kg.
In Study 2 (North American RCT), patients were randomized to receive a single administration of either RUCONEST 50 IU/kg (N=12), RUCONEST 100 IU/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 IU/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 : MeanVAS 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.
REFERENCES
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. Severe thrombus formation of Berinert® HS. Deutsches Ärzteblatt. 2000; 97:B-864.
7. Horstick, G et al. Application of C1-esterase inhibitor During Reperfusion of Ischemic Myocardium: Dose-Related Beneficial Versus Detrimental Effects. Circulation. 2001;104:3125-3131.
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:
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:
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:
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 Salix Pharmaceuticals, Inc. at 1-800-508-0024.
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.Salix.com or call 1-800-508-0024
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.
 |
Step 2: Inspect the RUCONEST vial. Do not use if:
 |
Step 3: Wash hands.
 |
DOSAGE VERIFICATION
Discuss this section with your healthcare provider to ensure that the correct dose of RUCONEST is administered.
| Body weight | RUCONEST dose for intravenous injection | Volume (mL) of reconstituted solution (150 IU/mL) to be administered |
| < 84 kg (185.2 lb) | 50 IU per kg of body weight | Body weight in kg divided by 3 |
| ≥ 84 kg (185.2 lb) | 4200 IU (2 vials) | 28 mL |
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 20°C-25°C or 68°F-77°F.)
The RUCONEST vial is for single-use only.
Step 2: Place the 2 RUCONEST vials and the diluent vial on a flat surface and remove the flip caps on each vial
 |
Step 3: Peel back the covers from the clear plastic vial adapter 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.
 |
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.
 |
Step 8: Transfer the diluent to the RUCONEST vial.
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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.
![RUCONEST (C1 esterase inhibitor [recombinant])Figure 9 IllustratioTransfer the diluent to the RUCONEST vial - Illustrationn](https://www.rxlist.com/images/rxlist/%0D%0A%0D%0Aruconest11.gif) |
Step 10: Inspect RUCONEST vial(s) visually.
 |
Step 11: With the syringe still connected to the RUCONEST vial, turn the vial upside down.
 |
Step 12: Repeat Step 11 and withdraw additional reconstituted RUCONEST from the second RUCONEST vial (if needed).
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.
 |
Step 2: Clean surface.
Step 3: Prime the infusion set.
As instructed by your healthcare provider:
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Step 4: Prepare the approved IV injection site.
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Step 5: Start infusion.
Follow the instructions provided by your healthcare provider.
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Step 6: Cover the injection site and clean up.
After all of the RUCONEST has been infused:
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POST-ADMINISTRATION
The procedures below are provided as general guidelines for after the infusion of RUCONEST.
Record each injection into treatment journal.
This Patient Package Insert has been approved by the US Food and Drug Administration.
