Alpha1-Proteinase Inhibitor

Hypersensitivity reactions have been reported in patients following administration of ARALAST/ARALAST NP [see WARNINGS AND PRECAUTIONS].

No serious adverse reactions related to the use of ARALAST NP were reported in clinical trials.The most common adverse reactions occurring in ≥ 5% of infusions in clinical trials were headache, musculoskeletal discomfort, vessel puncture site bruise, nausea, and rhinorrhea.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, 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 safety of ARALAST NP was evaluated in a total of 38 subjects with severe congenital Alpha1-PI deficiency (pre-augmentation therapy serum levels of Alpha1-PI of less than 11 microM) in two clinical trials. The crossover trial was a multicenter, randomized, double-blind, single-dose pharmacokinetic (PK) comparability trial conducted in 25 subjects with severe congenital Alpha1-PI deficiency to evaluate the pharmacokinetics of ARALAST NP (test drug, 60 mg/kg body weight) as compared to ARALAST (reference drug, 60 mg/kg body weight), each infused at a rate of 0.2 mL/kg body weight/minute. The BAL trial was a multicenter, open-label, non-randomized trial in 13 subjects with severe congenital Alpha1-PI deficiency to determine the safety and effects of weekly augmentation therapy with ARALAST NP (60 mg/kg body weight/week) administered at a rate of 0.2 mL/kg body weight/minute in elevating Alpha1-PI levels in serum and epithelial lining fluid (ELF).

In both trials, there were no deaths and no serious adverse reactions associated with ARALAST NP or ARALAST administration. None of the subjects withdrew from the trial due to an adverse reaction. There was no reduction in infusion rate at 0.2 mL/kg body weight/min or infusion discontinuation/interruption due to an adverse reaction, except for one subject in the crossover trial who experienced pain at infusion site during ARALAST administration.

Table 1 summarizes the number of subjects, the total number of infusions, and the rate of adverse reactions (ARs) associated with ARALAST NP or ARALAST treatment for each clinical trial.

Table 1 : Number of Subjects /Infusions /Adverse Reactions (ARs)a Occurring during ARALAST NP or ARALAST Treatment

The most common ARs (defined as adverse reactions occurring in ≥ 5% of infusions) in each clinical trial are shown in Table 2.

Table 2 : Adverse Reactions (ARs)a Occurring in ≥ 5% of Infusions

ARALAST was evaluated for up to 96 weeks in 27 subjects with a congenital deficiency of Alpha1-PI and clinically evident emphysema. During the initial 10 weeks of the trial, subjects were randomized to receive either ARALAST or a commercially available preparation of Alpha1-PI (PROLASTIN).

During the entire period of administration of ARALAST, the most common adverse reactions occurring at a rate of > 0.5% of infusions included pharyngitis (1.2%), headache (0.8%), and cough increased (0.5%). Adverse reactions that occurred at rates < 0.5% included somnolence, rash, tinnitus, back pain, chest pain, peripheral edema, dizziness, insomnia, bronchitis, abdomen enlarged, abdominal pain, allergic reaction, pruritus, chills, fever, vasodilation, nausea, hypertonia, hypesthesia, nervousness, asthma, dyspnea, lung disorder, abnormal vision, conjunctivitis, and dysmenorrhea.

Twenty-six (26) of 27 (96.3%) subjects experienced a total of 94 upper and lower respiratory-tract infections during the 96-week trial (median: 3.0; range: 1 to 8; mean ± SD: 3.6 ± 2.3 infections). Twentyeight (29.8%) of the respiratory infections occurred in 19 (70.4%) subjects during the first 24 weeks of the 96-week trial suggesting that the risk of infection did not change with time on ARALAST. In a posthoc analysis, subjects experienced a range of 0 to 8 exacerbations of COPD over the 96-week trial with a median of less than one exacerbation per year (median: 0.61; mean ± SD: 0.83 ± 0.87 exacerbations per year).

Treatment-emergent elevations ( > two times the upper limit of normal) in aminotransferases (ALT or AST), up to 3.7 times the upper limit of normal, were noted in 3 of 27 (11.1%) subjects. Elevations were transient lasting three months or less. No subject developed any evidence of viral hepatitis or hepatitis seroconversion while being treated with ARALAST, including 13 evaluable subjects who were not vaccinated against hepatitis B.

No clinically relevant alterations in blood pressure, heart rate, respiratory rate, or body temperature occurred during infusion of ARALAST. Mean hematology and routine clinical chemistry (other than ALT) laboratory parameters were little changed over the duration of the trial, with individual variations not clinically meaningful.

There were no serious adverse reactions or seroconversions reported for the ARALAST group during the 96 week trial period. No subject developed antibodies to Alpha1-PI.

a. 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 ARALAST NP with the incidence of antibodies to other products may be misleading.

b. Immunogenicity of ARALAST NP was evaluated in the BAL trial. None of the treated subjects developed antibodies against ARALAST NP.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ARALAST NP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular Disorders: Flushing

Gastrointestinal Disorders: Vomiting, Diarrhea

Skin and Subcutaneous Tissue Disorders: Urticaria

Musculoskeletal and Connective Tissue Disorders: Myalgia

General and Administration Site Conditions: Injection site reaction, Fatigue, Malaise, Asthenia, Feeling abnormal

(al fa won PRO tee in ase in HI bi tor)

• Aralast NP
• Glassia
• Prolastin-C
• Zemaira

Alpha1-proteinase inhibitor deficiency: Long-term augmentation and maintenance therapy in adults with severe hereditary deficiency of alpha1-antitrypsin (AAT) with clinically evident emphysema.

Limitations of use:

Clinical data demonstrating the long-term effects of chronic augmentation or maintenance therapy of individuals with alpha1-proteinase inhibitor are not available.

The effect of augmentation therapy with any alpha1-proteinase inhibitor on pulmonary exacerbations and on the progression of emphysema in AAT deficiency has not been demonstrated in randomized, controlled clinical trials.

Alpha1-proteinase inhibitors are not indicated as therapy for patients with lung disease in whom hereditary AAT deficiency has not been established.

Hypersensitivity to any component of the formulation or other A1-proteinase inhibitor products; IgA deficient patients with known anti-IgA antibody.

Refer to adult dosing.

For IV infusion only. Do not mix with other agents or solutions. If adverse reactions occur during administration, rate may be decreased or temporarily interrupted. Some products require an in-line filter for administration; consult specific product labeling.

Aralast NP, Glassia: Infuse at rate of ≤0.2 mL/kg/minute. Glassia may be self-administered by the patient/caregiver at home after appropriate training

Prolastin-C, Zemaira: Infuse at ~0.08 mL/kg/minute (rate may be increased or decreased based on patient comfort).

Concerns related to adverse effects:

• Hypersensitivity: Severe hypersensitivity and anaphylactic reactions may occur; stop infusion promptly for acute hypersensitivity; immediate treatment (including epinephrine and/or other supportive therapy) should be available. May contain trace amounts of IgA; patients with known anti-IgA antibody, which may be present in patients with selective or severe IgA deficiency, have an increased risk of developing potentially severe hypersensitivity and anaphylactic reactions.

Disease-related concerns:

• Fluid overload: Plasma volume may increase following infusion; use with caution in patients at risk for fluid overload.

Dosage form specific issues:

• Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease (eg, viruses and theoretically the Creutzfeldt-Jakob disease [CJD]). Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.

Alpha1-PI serum levels; lung function; vital signs during infusion