PROLASTIN-C Powder for solution for injection Ref.[27444] Active ingredients: Alfa1 antitrypsin

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 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 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 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).

The most serious adverse reaction observed during clinical trials with PROLASTIN-C was an abdominal and extremity rash in one subject [see Warnings and Precautions (5.1)].

The most common adverse reaction observed at a rate of >5% in subjects receiving PROLASTIN-C was upper respiratory tract infection.

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.

Two separate 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, 62 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 for adverse reactions (as defined in the footnote to Table 1) occurring during each 8 week double-blind crossover treatment period, as shown in Table 1.

Table 1. Adverse Reactions Occurring during the First 8 Weeks of Each Double-Blinded Treatment:

^* 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 2 below displays the adverse reaction (defined as per Table 1) rate as a percentage of infusions received during the 8 weeks of each double-blinded treatment.

Table 2. 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 3 below displays the adverse reactions occurring in two or more subjects during the single-arm open-label trial.

Table 3. 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 with the incidence of antibodies to other products may be misleading.

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, none of 24 subjects developed antibodies to PROLASTIN-C.

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.

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

Risk Summary

There are no data with PROLASTIN-C use in pregnant women to inform a drug-associated risk. 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. 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.

Risk Summary

There is no information regarding the presence of PROLASTIN-C in human milk, the effect 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 and any potential adverse effects on the breastfed infant from PROLASTIN-C.

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

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.