Ruconest (Page 2 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. Studies performed in rats and rabbits at doses up to 12.5 times the human dose of 50 U/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.

8.2 Labor and Delivery

The safety and efficacy of RUCONEST administration prior to or during labor and delivery have not been established. Use only if clearly needed.

8.3 Nursing Mothers

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.

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 (Log10 )

Step

MLV a

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

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