PROLASTIN-C is an Alpha1-Proteinase Inhibitor (Human) indicated for chronic
augmentation and maintenance therapy in adults with clinical evidence of emphysema due to
severe hereditary deficiency of alpha1-proteinase inhibitor (Alpha1-PI; the deficiency
condition is also known as alpha1-antitrypsin deficiency and AAT deficiency).
PROLASTIN-C 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 PROLASTIN-C, on
pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency
has not been conclusively demonstrated in randomized, controlled clinical trials.
• Clinical data demonstrating the long-term effects of chronic augmentation or
maintenance therapy with PROLASTIN-C are not available.
• PROLASTIN-C is not indicated as therapy for lung disease in patients in whom severe
Alpha1-PI deficiency has not been established.

PROLASTIN-C is available as a lyophilized powder in a single-use vial of approximately
1,000 mg. Reconstitute with Sterile Water for Injection, USP, provided in a separate 20 mL
vial.
Posology
For intravenous use only.
The recommended dose of PROLASTIN-C 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 shows the amount of functionally
active Alpha1-PI in milligrams (as determined by the capacity to neutralize porcine
pancreatic elastase).
Method of administration
Visually inspect parenteral drug products for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Infuse PROLASTIN-C 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.
Infuse PROLASTIN-C separately, without mixing with other agents or diluting solutions.
Elderly population
Clinical studies of PROLASTIN-C 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.

Paediatric population
Safety and effectiveness in the paediatric population have not been established.

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 urticarial; flushing; swollen lips,
tongue or uvula; wheezing; tightness of the chest; dyspnea; hypotension; and syncope. If
hypersensitivity symptoms occur, promptly stop the infusion and begin appropriate therapy.
Have epinephrine and other appropriate therapy available for the treatment of any acute
anaphylactic or anaphylactoid reaction.
PROLASTIN-C 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.
Transmissible infectious agents
Because PROLASTIN-C 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.

PROLASTIN-C should be given alone, without mixing with other agents or diluting
solutions.

Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with
PROLASTIN-C. It is not known whether PROLASTIN-C can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PROLASTIN-C
should be given to a pregnant woman only if clearly needed.
Lactation
There is insufficient/limited information on the excretion of Alpha1-Proteinase Inhibitor
(Human) in human or animal breast milk. A risk to the suckling child cannot be excluded. A
decision on whether to continue/discontinue breast-feeding or to continue/discontinue
therapy with PROLASTIN-C should be made taking into account the benefit of breastfeeding
to the child and the benefit of PROLASTIN-C therapy to the woman.

Use of PROLASTIN-C has not been reported to impair the ability to operate a motor vehicle
or the capacity to operate machinery.

The most serious adverse reaction observed during clinical trials with PROLASTIN-C was
an abdominal and extremity rash in one subject. The most common adverse reactions
observed at a rate of > 5% in subjects receiving PROLASTIN-C LIQUID1 were diarrhea and
fatigue, each of which occurred at a rate of 6% (two subjects each).
The most common adverse reaction observed at a rate of ≥ 5% in subjects receiving
PROLASTIN-C was upper respiratory tract infection.
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 1: Adverse Reactions Occurring in >5% of Subjects during the Double-
Blinded Crossover Treatment

* An adverse reaction is defined as any adverse event that occurred where either a) the
event was not considered “unrelated” to administration of the product, or b) the
occurrence was during or within 72 hours of the end of the previous infusion of the
product, or c) the investigator's causality assessment of the event was missing or
indeterminate, or d) the incidence during treatment with 1 investigational product was
130% or more of the incidence during treatment with the other investigational product.
† Source: the randomized double-blinded comparator trial of PROLASTIN-C LIQUID vs
PROLASTIN-C.
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.

Table 2: Adverse Reaction Frequency as a Percent of All Infusions and
Occurring More than Once in the PROLASTIN-C LIQUID Group
during the 16 Week Double Blinded Treatment Period

* Source: the randomized double-blinded comparator trial of PROLASTIN-C LIQUID vs
PROLASTIN-C.
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
194 considered to be serious, except for one event after PROLASTIN-C treatment during the
195 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.

* An adverse reaction is defined as any adverse event where either a) the incidence with
PROLASTIN-C was greater than with PROLASTIN, or b) the occurrence was within 72
hours of treatment, or c) the event was otherwise considered related or possibly related to
the drug.
† Source: the randomized double-blinded comparator trial.

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 4: Adverse Reaction Frequency as a Percent of All Infusions during the First
8 Weeks of Each Double-Blinded Infusion Treatment

* Source: the randomized double-blinded comparator trial.

Table 5 below displays the adverse reactions occurring in two or more subjects during the
215 single-arm open-label trial.
Table 5: Adverse Reactions Occurring in Two or More Subjects (>5%) during
the 20 Week Single-Arm Open-Label Trial

* An adverse reaction is defined as any adverse event that occurred where either a) the
occurrence was within 72 hours of treatment, or b) the event was otherwise considered
related or possibly related to the drug.
† Source: 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.
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 post marketing 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

To report any side effect(s):
• Saudi Arabia:
• The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc
• Other GCC States:
• Please contact the relevant competent authority.

No data are available regarding overdose in humans.

Pharmacotherapeutic Group: alfa1 antitrypsin. ATC code: B02AB02
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. Because emphysema affects many, but
not all individuals with the more severe genetic variants of Alpha1-PI deficiency,
augmentation therapy with Alpha1-Proteinase Inhibitor (Human) 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.
Approximately 95% of all severely deficient patients are homozygous for the PiZ allele.
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, 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 antineutrophil
elastase protection, 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 to evolve as described in the “proteaseantiprotease
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 (Alpha1-Proteinase Inhibitor [Human])
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.
Chronic augmentation therapy with the predecessor product, PROLASTIN® (Alpha1-
Proteinase Inhibitor [Human]), administered weekly at a dose of 60 mg/kg body weight,
results in significantly 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. 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.

The pharmacokinetic (PK) study was a randomized, double-blind, crossover trial comparing
PROLASTIN-C LIQUID(2) to PROLASTIN-C 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
(2) PROLASTIN-C LIQUID is not available in Saudi Arabia.

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 concentrationby-
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.

Table 7: Results of Statistical Analysis of Pharmacokinetic Parameters at
Steady-State (PK Population)

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.

Figure 1: Mean Serum-equivalent Alpha1-PI Concentration (functional activity)
vs. Time Curves Following Treatment with PROLASTIN-C LIQUID or
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.

Table 8: Pharmacokinetic Parameters of Alpha1-PI in Plasma

The key pharmacokinetic parameter was the area under the plasma Alpha1-PI concentrationby-
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.

The active ingredient, alpha1-proteinase inhibitor, is obtained from human plasma and
behaves like endogenous plasma constituents. Administration of a single dose of Alpha1-
Proteinase Inhibitor (Human) to various animal species, as well as administration of daily
doses during five consecutive days to rabbits, showed no indications of toxic effects.
Additional preclinical studies with repeated dosing (chronic toxicity, carcinogenicity,
reproduction toxicity) were not conducted. These studies cannot usefully be performed in
conventional animal models, as antibodies are expected to be formed as a result of
administration of heterologous human protein.

Sodium monobasic phosphate
Sodium chloride
Solvent: water for injection

Do not mix with other solutions or medicinal products.

Store PROLASTIN-C at temperatures not to exceed 25°C (77°F) for the period indicated by
the expiration date on its label.
Avoid freezing as breakage of the diluent bottle might occur.

PROLASTIN-C powder is supplied in clear type I glass vials closed with chlorobutyl
stoppers. Each vial contains 1,000 mg Alpha1-Proteinase Inhibitor (Human).
Sterile Water for Injection, USP, is supplied in type I glass vials closed with butyl rubber
stoppers, protected with aluminum flip-off caps. Each vial contains 20 mL sterile water for
injection.
PROLASTIN-C is supplied in a kit containing a single-use vial of PROLASTIN-C,
lyophilized powder, one 20 mL vial of Sterile Water for Injection, USP, a transfer needle,
and a filter needle. The total Alpha1-PI functional activity, in milligrams, is stated on the
label of the PROLASTIN-C vial and carton.
Components of the packaging do not contain natural rubber latex.

Reconstitution
1. Allow unopened PROLASTIN-C and diluent vials to warm up to room temperature
before reconstitution.
2. Remove the plastic flip tops from each vial.
3. Swab the exposed stopper surfaces with alcohol and allow to dry.
4. Remove the plastic cover from the short end of the transfer needle. Insert the exposed end
of the needle through the center of the stopper in the diluent vial.
5. Remove the cover at the other end of the transfer needle by twisting it carefully.

6. Invert the diluent vial and insert the attached needle into the PROLASTIN-C vial at a 45°
angle (Figure below). This will direct the stream of diluent against the wall of the product
vial and minimize foaming. The vacuum will draw the diluent into the PROLASTIN-C
vial.
7. Remove the diluent vial and transfer needle.
8. Immediately after adding the diluent, swirl vigorously for 10–15 seconds to thoroughly
break-up cake, then swirl continuously until the powder is completely dissolved (Figure
below). Some foaming will occur, but does not affect the quality of the product.
9. Inspect the reconstituted PROLASTIN-C visually for particulate matter and discoloration
prior to pooling. A few small particles may remain after reconstitution. If particles are
visible, remove by passage through a sterile filter, such as a 15 micron filter used for
administering blood products (not supplied).
10. Pool reconstituted PROLASTIN-C from several vials into an empty, sterile intravenous
solution container using aseptic technique. Use the sterile filter needle provided for this
purpose.
11. Keep reconstituted solution at room temperature for administration within three hours.