Aralast NP: Package Insert and Label Information

ARALAST NP- alpha-1-proteinase inhibitor (human)
Baxalta U.S. Inc.

1 INDICATIONS AND USAGE

ARALAST NP is an Alpha1 -Proteinase Inhibitor (Alpha1 -PI) indicated for chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of Alpha1 -PI (alpha1 -antitrypsin deficiency). ARALAST NP increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1 -PI.

The effect of augmentation therapy with any Alpha1 -PI, including ARALAST NP, on pulmonary exacerbations and on the progression of emphysema in alpha1 -antitrypsin deficiency has not been conclusively demonstrated in randomized, controlled clinical trials.

Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy with ARALAST NP or ARALAST are not available.

ARALAST NP is not indicated as therapy for lung disease in patients in whom severe congenital Alpha1 -PI deficiency has not been established.

2 DOSAGE AND ADMINISTRATION

For Intravenous Use Only

2.1 Dosage

  • Dose ranging studies using efficacy endpoints have not been performed.
  • Administer 60 mg/kg body weight of ARALAST NP once weekly by intravenous infusion.

2.2 Reconstitution

  1. Use aseptic technique.
  2. Allow ARALAST NP and diluent to reach room temperature before reconstitution.
  3. Remove caps from the diluent and product vials.
  4. Swab the exposed stopper surfaces with alcohol.
  5. Remove cover from one end of the double-ended transfer needle. Insert the exposed end of the needle through the center of the stopper in the diluent vial.
  6. Remove plastic cap from the other end of the double-ended transfer needle now seated in the stopper of the diluent vial. To reduce any foaming, invert the vial of diluent and insert the exposed end of the needle through the center of the stopper in the product vial at an angle, making certain that the diluent vial is always above the product vial. The angle of insertion directs the flow of diluent against the side of the product vial. Refer to Figure below. The vacuum in the vial is sufficient to allow transfer of all of the diluent.Image
  7. Disconnect the two vials by removing the diluent vial from the transfer needle. This allows any remaining low pressure in the product vial to equalize. Next, remove the double-ended transfer needle from the product vial and discard the needle into the appropriate safety container.
  8. Let the vial stand until most of the contents is in solution, then GENTLY swirl until the powder is completely dissolved. Reconstitution requires no more than five minutes for a 0.5 gram vial and no more than 10 minutes for a 1 gram vial. Note: Do not shake the content of the vial. Do not invert the vial until ready to withdraw content.
  9. Reconstituted product is a colorless or slightly yellow to yellow-green solution.
  10. A few small visible particles may occasionally remain in the reconstituted product. These will be removed by the sterile 20 micron filter supplied with the product.
Image

2.3 Administration

For intravenous infusion

  1. Inspect the reconstituted product visually for particulate matter and discoloration prior to administration.
  2. Several vials may be pooled into an empty, sterile intravenous solution container using aseptic technique and a sterile 20 micron filter supplied with the product.
  3. Administer ARALAST NP within three hours after reconstitution to reduce the risk of harmful microbial growth. Discard any unused contents.
  4. Administer ARALAST NP alone, without mixing with other agents or diluting solutions.

Infusion Rate

  • Administer ARALAST NP at a rate not to exceed 0.2 mL per kg body weight per minute, and as determined by the response and comfort of the patient.
  • Reduce the infusion rate or halt the infusion if adverse reactions occur. Resume the infusion at a rate tolerated by the patient after symptoms subside.

3 DOSAGE FORMS AND STRENGTHS

ARALAST NP is available as a lyophilized powder in single dose vials containing 0.5 gram or 1 gram of functional Alpha1 -PI.

4 CONTRAINDICATIONS

ARALAST NP is contraindicated in immunoglobulin A (IgA) deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

ARALAST NP may contain trace amounts of IgA. Patients with known antibodies to IgA, which can be present in patients with selective or severe IgA deficiency, have a greater risk of developing severe hypersensitivity and anaphylactic reactions. Closely follow the recommended infusion rate [see Dosage and Administration (2.3)]. Monitor vital signs continuously and observe the patient carefully throughout the infusion. Discontinue the infusion if hypersensitivity symptoms occur and administer appropriate emergency treatment. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.

5.2 Transmission of Infectious Agents

Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections and by inactivating and removing certain viruses during the manufacturing process. Despite these measures, such products may still potentially transmit human pathogenic agents.

No seroconversions for hepatitis B or C (HBV or HCV) or human immunodeficiency virus (HIV) or any other known infectious agent were reported with the use of ARALAST NP during clinical studies.

All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-800-423-2090 (in the U.S.).

6 ADVERSE REACTIONS

Hypersensitivity reactions have been reported in patients following administration of ARALAST/ARALAST NP [see Warnings and Precautions (5.1)].

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.

6.1 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)* Occurring during ARALAST NP or ARALAST Treatment
Crossover Trial BAL Trial
ARALAST NP ARALAST ARALAST NP
*
An adverse reaction (AR) is any adverse event which met any of the following criteria: (a) an adverse event that began during infusion or within 72 hours following the end of product infusion, or (b) an adverse event considered by the investigator to be at least possibly related to product administration, or (c) an adverse event for which causality assessment was missing or indeterminate.
A mild reaction was defined as a transient discomfort that does not interfere in a significant manner with the subject’s normal functioning level, or an event that resolves spontaneously or may require minimal therapeutic intervention
A moderate reaction was defined as an event that is considered related to study product and that produces limited impairment of function and can require therapeutic intervention, or that produces no sequelae
§
A severe reaction was defined as an event that is considered related to study product and that results in a marked impairment of function and can lead to temporary inability to resume usual life pattern, or that produces sequelae which requires prolonged therapeutic intervention
No. of subjects treated 25 25 13
No. of infusions 25 25 104
No. (%) of subjects with serious ARs 0 (0%) 0 (0%) 0 (0%)
No. of serious ARs 0 0 0
No. (%) of subjects with non-serious ARs 12 (48%) 13 (52%) 4 (31%)
No. of non-serious ARs 26 21 14
No. (%) of Mild ARs 21 (81%) 16 (76%) 8 (57%)
No. (%) of Moderate ARs 5 (19%) 5 (24%) 5 (36%)
No. (%) of Severe § ARs 0 (0%) 0 (0%) 1 (7%)

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)* Occurring in ≥5% of Infusions
Crossover Trial (Number of Subjects = 25; Number of infusions per product = 25) BAL Trial (Number of Subjects = 13; Number of infusions = 104)
Reaction ARALAST NP N (%) ARALAST N (%) ARALAST NP N (%)
*
An adverse reaction (AR) is any adverse event which met any of the following criteria: (a) an adverse event that began during infusion or within 72 hours following the end of product infusion, or (b) an adverse event considered by the investigator to be at least possibly related to product administration, or (c) an adverse event for which causality assessment was missing or indeterminate.
Expressed as number of events (N) divided by total number of infusions, then multiplied by 100.
Headache 4 (16%) 3 (12%) 0 (0%)
Musculoskeletal discomfort 4 (16%) 2 (8%) 0 (0%)
Vessel puncture site bruise 2 (8%) 4 (16%) 0 (0%)
Lethargy 0 (0%) 2 (8%) 0 (0%)
Nausea 2 (8%) 2 (8%) 0 (0%)
Rhinorrhea 1 (4%) 0 (0%) 6 (6%)

ARALAST versus PROLASTIN Trial

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). Twenty-eight (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 post-hoc 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.

Immunogenicity

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