2.1 Dose

• The recommended dose of PROLASTIN-C LIQUID is 60 mg/kg body weight administered intravenously once weekly.
  
  
• Dose ranging studies using efficacy endpoints have not been performed with any Alpha1-PI product.
  
  
• The carton and the label on each vial of PROLASTIN-C LIQUID show the actual amount of functionally active Alpha1-PI in milligrams (as determined by the capacity to neutralize porcine pancreatic elastase).

2.2 Preparation and Handling

1. Allow unopened PROLASTIN-C LIQUID to warm up to room temperature before administration.
   
2. Remove the plastic flip top from the vial.
   
3. Swab the exposed stopper surface with alcohol and allow to dry.
   
4. Inspect the PROLASTIN-C LIQUID visually for particulate matter and discoloration prior to pooling. The product may contain a few protein particles. The solution is clear, colorless or pale yellow or pale green. Do not use if the product is discolored or cloudy.
   
5. Pool PROLASTIN-C LIQUID from several vials to achieve the intended mg/kg body weight dose into an empty, sterile intravenous solution container using aseptic technique.
   
6. Keep pooled solution at room temperature for administration within three hours.
7. Discard unused portion.
   

2.3 Administration

• Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The product may contain a few protein particles. Do not use if discolored or cloudy.
• Filter the solution during administration using an intravenous administration set with a suitable 5 to 15 micron infusion filter (not supplied).
• Infuse PROLASTIN-C LIQUID separately, without mixing with other agents or diluting solutions.
• Infuse PROLASTIN-C LIQUID intravenously at 0.08 mL/kg/min as determined by patient response and comfort. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur. Monitor vital signs and observe the patient carefully throughout the infusion. Early signs and symptoms of hypersensitivity reactions may include pruritus; generalized urticaria; flushing; swollen lips, tongue, or uvula; wheezing; tightness of the chest; dyspnea; hypotension; and syncope. If hypersensitivity symptoms occur, promptly stop PROLASTIN-C LIQUID infusion and begin appropriate therapy. Have epinephrine and other appropriate therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. [see Patient Counseling Information (17)]

PROLASTIN-C LIQUID 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 potentially severe hypersensitivity and anaphylactic reactions.

5.2 Transmissible Infectious Agents

Because PROLASTIN-C LIQUID is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of transmission of infectious agents has been reduced by screening plasma donors for prior exposure to certain infectious agents, by testing for the presence of certain virus infections, and by including steps in the manufacturing process with the demonstrated capacity to inactivate and /or remove certain infectious agents. Despite these measures, this product may still potentially transmit disease.

Report all infections thought by a physician possibly to have been transmitted by this product to Grifols Therapeutics LLC (1-800-520-2807).

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

One clinical trial was conducted with PROLASTIN-C LIQUID: a 16 week, multicenter, randomized, double-blind crossover study to assess the safety, immunogenicity, and pharmacokinetic comparability of PROLASTIN-C LIQUID to PROLASTIN-C in 32 subjects.

Adverse reactions (as defined in the footnote to Table 1) occurring in >5% of subjects during the 16 week double-blind crossover treatment period are shown in Table 1.

Table 2 below displays the adverse reaction (defined as per Table 1) rate as a percentage of infusions received during the 16 week double-blinded treatment period.

A total of 23 COPD exacerbations were reported for a total of 18 individual subjects. Twelve subjects (12/32, 38%) during PROLASTIN-C LIQUID treatment experienced 13 COPD exacerbations, and 9 subjects (9/31, 29%) during PROLASTIN-C treatment had 10 COPD exacerbations. Three COPD exacerbations occurred during the Follow-Up Period after PROLASTIN-C LIQUID treatment and 1 COPD exacerbation occurred in the Follow-up period after PROLASTIN-C treatment. The overall rate of pulmonary exacerbations during treatment with either product was 1.9 exacerbations per subject-year. No exacerbation was considered to be serious, except for one event after PROLASTIN-C treatment during the Follow-Up period (due to hospitalization).

Two separate prior clinical trials were conducted with PROLASTIN-C: 1.) a 20 week, open-label, single arm safety study in 38 subjects (single-arm open-label trial), and 2.) a 16 week, randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN in 24 subjects, followed by an 8 week open-label treatment with PROLASTIN-C (randomized double-blinded comparator trial). Thus, a total of 93 subjects were exposed to PROLASTIN-C in clinical trials.

The most serious adverse reaction observed during clinical trials with PROLASTIN-C was an abdominal and extremity rash in one subject. The rash resolved subsequent to outpatient treatment with antihistamines and steroids. Two instances of a less severe, pruritic abdominal rash were observed upon rechallenge despite continued antihistamine and steroid treatment, which led to withdrawal of the subject from the trial.

Grifols assessed the randomized double-blinded comparator trial of PROLASTIN and PROLASTIN-C for adverse reactions (as defined in the footnote to Table 3) occurring during each 8 week double-blind crossover treatment period, as shown in Table 3.

Table 4 below displays the adverse reaction (defined as per Table 3) rate as a percentage of infusions received during the 8 weeks of each double-blinded treatment.

Table 5 below displays the adverse reactions occurring in two or more subjects during the single-arm open-label trial.

Ten exacerbations of chronic obstructive pulmonary disease were reported by 8 subjects in the 24 week crossover pharmacokinetic study. During the 16 week double-blind crossover phase, 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN-C treatment and 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN treatment. Two additional exacerbations in 2 subjects (8%) occurred during the 8 week open-label treatment period with PROLASTIN-C. The overall rate of pulmonary exacerbations during treatment with either product was 0.9 exacerbations per subject-year.

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 PROLASTIN-C LIQUID with the incidence of antibodies to other products may be misleading.

In the randomized, crossover pharmacokinetic clinical trial, no immunogenicity response was observed in subjects dosed with PROLASTIN-C LIQUID or PROLASTIN-C.

In the single-arm, open-label safety clinical trial, three treatment naïve subjects out of 36 subjects evaluated developed antibody to Alpha1-PI at week 24 after receiving PROLASTIN-C. A fourth subject (non-naïve) was positive prior to and after receiving PROLASTIN-C, but levels were unchanged during the study. None of the four antibody specimens was able to neutralize the protease inhibitor capacity of PROLASTIN-C. In the randomized, crossover pharmacokinetic clinical trial comparing PROLASTIN-C and PROLASTIN, none of 24 subjects developed antibodies to PROLASTIN-C.

6.2 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.

Expected postmarketing experience for PROLASTIN-C LIQUID is based on the reactions reported for PROLASTIN-C. The reactions which have been chosen for inclusion due to their seriousness, frequency of reporting, possible causal connection to PROLASTIN®-C, or a combination of these factors, are:

• General/Body as a Whole: Fatigue, malaise, influenza-like illness, pain, asthenia
• Immune system: Hypersensitivity including anaphylactoid/anaphylactic reactions
• Cardiovascular: Tachycardia
• Musculoskeletal: Arthralgia, myalgia
• Gastrointestinal: Vomiting, diarrhea
• Investigation: Blood pressure increased

8.1 Pregnancy

Risk Summary

There are no data with PROLASTIN-C LIQUID use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with PROLASTIN-C LIQUID. It is not known whether PROLASTIN-C LIQUID can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PROLASTIN-C LIQUID should be given to a pregnant woman only if clearly needed.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of PROLASTIN-C LIQUID in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PROLASTIN-C LIQUID and any potential adverse effects on the breastfed infant from PROLASTIN-C LIQUID or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

8.5 Geriatric Use

Clinical studies of PROLASTIN-C LIQUID did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

12.1 Mechanism of Action

Alpha1-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha1-PI. Smoking is an important risk factor for the development of emphysema in patients with Alpha1-PI deficiency.(1,2) Because emphysema affects many, but not all individuals with the more severe genetic variants of Alpha1-PI deficiency, augmentation therapy with Alpha1-PI is indicated only in patients with severe Alpha1-PI deficiency who have clinically evident emphysema.

Only some Alpha1-PI alleles are associated with clinically apparent Alpha1-PI deficiency.(3,4) Approximately 95% of all severely deficient patients are homozygous for the PiZ allele.(4) Individuals with the PiZZ variant typically have serum Alpha1-PI levels less than 35% of the average normal level. Individuals with the Pi(null)(null) variant have undetectable Alpha1-PI protein in their serum. Individuals with these low serum Alpha1-PI levels, i.e., less than 11 µM, have a markedly increased risk for developing emphysema over their lifetimes. In addition, PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 µM,(5) are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha1-PI levels are above or below 11 µM.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with Alpha1-PI deficiency. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with any Alpha1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been demonstrated in adequately powered, randomized controlled, clinical trials. Although the maintenance of blood serum levels of Alpha1-PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection,(6) this has not been proven. Individuals with severe Alpha1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with Alpha1-PI above 11 µM have emphysema attributed to Alpha1-PI deficiency. These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of Alpha1-PI during augmentation therapy.

The pathogenesis of emphysema is understood as described in the “protease-antiprotease imbalance” model. Alpha1-PI is understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE). Normal healthy individuals produce sufficient Alpha1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of the lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals who are severely deficient in endogenous Alpha1-PI are unable to maintain an appropriate antiprotease defense, and, in addition, they have been shown to have increased lung epithelial lining fluid neutrophil and NE concentrations. Because of these factors, many (but not all) individuals who are severely deficient in endogenous Alpha1-PI are subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. PROLASTIN-C LIQUID serves as Alpha1-PI augmentation therapy in the patient population with severe Alpha1-PI deficiency and emphysema, acting to increase and maintain serum and lung epithelial lining fluid levels of Alpha1-PI.

12.2 Pharmacodynamics

Chronic augmentation therapy with the predecessor product, PROLASTIN®, administered weekly at a dose of 60 mg/kg body weight, results in increased levels of Alpha1-PI and functional anti-neutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing therapy with PROLASTIN.(7) However, the clinical benefit of the increased levels at the recommended dose has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha1-PI product.

PROLASTIN-C LIQUID increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels.

12.3 Pharmacokinetics

The pharmacokinetic (PK) study was a randomized, double-blind, crossover trial comparing PROLASTIN-C LIQUID to PROLASTIN-C (Alpha1-Proteinase Inhibitor [Human]) conducted in 32 adult subjects age 44 to 71 years with severe Alpha1-PI deficiency. Eighteen subjects were male and 14 subjects were female. Sixteen subjects were randomized to each treatment sequence. All but one subject had the PiZZ genotype and the remaining subject was PiSZ. Twenty-eight subjects had received prior Alpha1-PI augmentation therapy and 4 subjects were naïve to Alpha1-PI augmentation therapy. Study subjects were randomly assigned to receive either 60 mg/kg body weight of functional PROLASTIN-C LIQUID or PROLASTIN-C weekly by intravenous infusion during the first 8-week treatment period. Following the last dose in the first 8-week treatment period, subjects underwent serial blood sampling for PK analysis and then crossed over to the alternate treatment for the second 8-week treatment period. Following the last treatment in the second 8-week treatment period, subjects underwent serial blood sampling for PK analysis. In addition, blood samples were drawn for trough levels before infusion at Weeks 6, 7, 8, and 9, as well as before infusion at Weeks 14, 15, 16, and 17. A final PK sample was drawn at Week 20 (4 weeks after the last dose) to correct for endogenous Alpha1-PI levels.

The key pharmacokinetic parameter was the area under the serum Alpha1-PI concentration-by-antigenic-assay-time curve (AUC0-7days) following 8 weeks of treatment with PROLASTIN-C LIQUID or PROLASTIN-C. The 90% confidence interval (1.03-1.08) for the ratio of AUC0-7days for PROLASTIN-C LIQUID and PROLASTIN-C indicated that the 2 products are bioequivalent, i.e. the entire range falls within the 0.80 – 1.25 interval. AUC0-7days of the serum-equivalent Alpha1-PI concentration by functional assay and Cmax by antigenic and functional assays gave comparable results for PROLASTIN-C LIQUID and PROLASTIN-C, as shown in Table 7.

The half life (t1/2) for antigenic content was comparable, specifically 156.39 hours versus 164.10 hours for PROLASTIN-C LIQUID versus PROLASTIN-C, respectively. Similar half life was also observed when assessed by functional activity between PROLASTIN-C LIQUID versus PROLASTIN-C (126.57 hours versus 126.82 hours respectively).

Figure 1 shows the serum-equivalent concentration (functional activity) vs. time curves of Alpha1-PI after intravenous administration of PROLASTIN-C LIQUID and PROLASTIN-C.

Serum trough levels measured at steady state during the PK study using an antigenic content assay showed PROLASTIN-C LIQUID resulted in a mean trough of 17.7 µM and PROLASTIN-­C resulted in a mean trough of 16.9 µM.

A randomized, double-blind, crossover pharmacokinetic (PK) study comparing PROLASTIN-C to PROLASTIN was conducted in 24 adult subjects age 40 to 72 with severe Alpha1-PI deficiency. Ten subjects were male and 14 subjects were female. All but one subject had the PiZZ genotype and the remaining subject had PiSZ. All subjects had received prior Alpha1-PI therapy with PROLASTIN for at least 1 month. The double-blind portion of the study was designed the same as the randomized, double-blind, crossover PK study comparing PROLASTIN-C LQUID to PROLASTIN-C described above.

The pharmacokinetic parameters of Alpha1-PI in plasma, based on serum-equivalent functional activity assays, showed comparability between PROLASTIN-C treatment and PROLASTIN treatment, as shown in Table 8.

The key pharmacokinetic parameter was the area under the plasma Alpha1-PI concentration-by-antigenic-assay-time curve (AUC0-7days) following 8 weeks of treatment with PROLASTIN-C or PROLASTIN. The 90% confidence interval (0.97-1.09) for the ratio of AUC0-7days for PROLASTIN-C and PROLASTIN indicated that the 2 products are bioequivalent, i.e. the entire range falls within the 0.80 – 1.25 interval.

Serum-equivalent trough levels measured during the crossover PK study via an antigenic content assay showed PROLASTIN-C treatment resulted in a mean trough of 16.9 ± 2.3 µM and PROLASTIN resulted in a mean trough of 16.7 ± 2.7 µM. Using the functional activity assay, PROLASTIN-C resulted in a mean trough of 11.8 ± 2.2 µM and PROLASTIN resulted in a mean trough of 11.0 ± 2.2 µM.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, mutagenesis, and impairment of fertility studies were not performed; PROLASTIN-C LIQUID is a biologic purified from human plasma.

13.2 Animal Toxicology and/or Pharmacology

Intravenous administration of five daily doses of PROLASTIN-C LIQUID to rabbits at a dose up to 600 mg/kg per day (10-fold higher dose than the recommended human dose of 60 mg/kg administered weekly), did not result in any signs of toxicity. Further, there were no differences in safety and tolerability of PROLASTIN-C and PROLASTIN-C LIQUID in nonclinical testing.