2.1 Preparation and Reconstitution

• Check the expiration date on the vial label and carton. Do not use Zemaira after the expiration date.
• Reconstitute prior to use.
• Reconstitute Zemaira using aseptic technique to maintain product sterility.
• Inspect the reconstituted solution prior to administration. The solution should be clear, colorless to slightly yellow, and free from visible particles.
• Administer Zemaira at room temperature within 3 hours after reconstitution. Reconstituted Zemaira may be stored at room temperature. Do not freeze the reconstituted solution.

Follow the steps below to reconstitute Zemaira:

1. Ensure that the Zemaira (green cap) vial and diluent (white cap) vial are at room temperature.
2. Remove the plastic flip-top caps from the vials. Aseptically cleanse the rubber stoppers with antiseptic solution and allow them to dry.
Notes on Using the Transfer Device (Steps 3 through 7): The transfer device (Figure 1) provided in the Zemaira carton has a white (diluent) end with a double orifice and a green (Zemaira) end with a single orifice. Incorrect use of the transfer device will result in loss of vacuum and prevent transfer of the diluent, thereby prolonging or preventing reconstitution of Zemaira. The transfer device is sterile. Once the protective covers have been removed (Steps 3 and 4), do not touch the exposed ends of the spikes.	Figure 1
3. Remove the protective cover from the white (diluent) end of the transfer device. Insert the white end of the transfer device into the center of the stopper of the upright diluent vial (Figure 2).	Figure 2
4. Remove the protective cover from the green (Zemaira) end of the transfer device. Invert the diluent vial with the attached transfer device and, using minimum force, insert the green end of the transfer device into the center of the rubber stopper of the upright Zemaira vial (green top) (Figure 3). The flange of the transfer device should rest on the surface of the stopper so that the diluent flows into the Zemaira vial.	Figure 3
5. Allow the vacuum in the Zemaira vial to pull the diluent into the Zemaira vial.
6. During diluent transfer, wet the lyophilized cake completely by gently tilting the Zemaira vial (Figure 4). Do not allow the air inlet filter to face downward. Care should be taken not to lose the vacuum, as this will prolong or prevent reconstitution.	Figure 4
7. After diluent transfer is complete, the transfer device will allow filtered air into the Zemaira vial through the air filter; additional venting of the Zemaira vial is not required. When diluent transfer is complete, withdraw the transfer device from the diluent vial and discard the diluent vial and transfer device.
8. Gently swirl the Zemaira vial until the powder is completely dissolved (Figure 5). DO NOT SHAKE.	Figure 5

If more than 1 vial of Zemaira is needed to achieve the required dose, use aseptic technique to transfer the reconstituted solution from the vials into the administration container (e.g., empty intravenous bag or glass bottle).

2.2 Administration

• For intravenous use only.
• Do not mix Zemaira with other medicinal products. Administer Zemaira through a separate dedicated infusion line.
• Perform a visual inspection of the reconstituted solution. The solution should be clear, colorless to slightly yellow, and free from visible particles.
• Administer at room temperature within 3 hours after reconstitution.
• Filter the reconstituted solution during administration. To ensure proper filtration of Zemaira, use an intravenous administration set with a suitable 5 micron infusion filter (not supplied).
• Administer Zemaira intravenously at a rate of approximately 0.08 mL/kg/min as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg body weight will take approximately 15 minutes to infuse.
• Monitor closely the infusion rate and the patient's clinical state, including vital signs, throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
• Zemaira is for single use only. Following administration, discard any unused solution and all administration equipment in an appropriate manner as per local requirements.

5.1 Hypersensitivity to Other A1-PI Products

Caution should be used when administering Zemaira to individuals who have experienced anaphylaxis or severe systemic reaction to another A1-PI product. IF ANAPHYLACTIC OR SEVERE ANAPHYLACTOID REACTIONS OCCUR, DISCONTINUE THE INFUSION IMMEDIATELY. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. Zemaira is contraindicated in patients with a history of anaphylaxis or severe systemic reactions to Zemaira or A1-PI protein.

5.2 Hypersensitivity to IgA

Zemaira may contain trace amounts of IgA. Patients with selective or severe IgA deficiency can develop antibodies to IgA and, therefore, have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. IF ANAPHYLACTIC OR SEVERE ANAPHYLACTOID REACTIONS OCCUR, DISCONTINUE THE INFUSION IMMEDIATELY. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. Zemaira is contraindicated in IgA-deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

5.3 Transmissible Infectious Agents

Because Zemaira is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses, and theoretically the Creutzfeldt-Jakob disease [CJD] agent). The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Zemaira [see Description (11)]. Despite these measures, Zemaira, like other products made from human plasma, may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated.

All infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following clinical trials were conducted with Zemaira:

• Controlled, double-blind trial in 44 subjects, who received a weekly 60 mg/kg body weight dose of either Zemaira (30 subjects) or Prolastin® (a commercially available Alpha1-Proteinase Inhibitor [Human] product) (14 subjects) for 10 weeks, followed by an open-label phase in which 43 subjects received Zemaira weekly for 14 weeks;
• Open-label trial in 9 subjects who received a weekly 60 mg/kg body weight dose of Zemaira for 26 weeks, followed by a 7-week to 22-week extension;
• Crossover, double-blind trial in 18 subjects who received a single 60 mg/kg dose of Zemaira and a single 60 mg/kg dose of Prolastin;
• Open-label trial of 19 subjects who received a single 15 mg/kg (2 subjects), 30 mg/kg (5 subjects), 60 mg/kg (6 subjects), or 120 mg/kg (6 subjects) dose of Zemaira; and
• Post-Licensure Randomized, Placebo-Controlled Trial of Augmentation Therapy in Alpha-1 Protease Inhibitor Deficiency (RAPID), in 180 subjects who received a weekly 60 mg/kg body weight dose of either Zemaira (93 subjects) or placebo (87 subjects) for 24 months (referred to as years 1 and 2 in Table 3).
• Post-Licensure Open-label extension of the RAPID trial involving 140 subjects who had completed blinded treatment with Zemaira or placebo for 24 months in the RAPID trial and who entered the extension trial and received open-label Zemaira for up to an additional 24 months (referred to as years 3 and 4 in Table 3).

Table 1 summarizes the ARs, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in pre-licensure clinical trials of Zemaira.

Table 2 summarizes the ARs occurring in 5% or more (>3) subjects, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in clinical trials of Zemaira.

Diffuse interstitial lung disease was noted on a routine chest x-ray of one subject at Week 24. Causality could not be determined.

Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

In a retrospective analysis, during the 10-week blinded portion of the 24-week clinical trial, 6 subjects (20%) of the 30 treated with Zemaira had a total of 7 exacerbations of their chronic obstructive pulmonary disease (COPD). Nine subjects (64%) of the 14 treated with Prolastin had a total of 11 exacerbations of their COPD. The observed difference between groups was 44% (95% confidence interval [CI] from 8% to 70%). Over the entire 24-week treatment period, of the 30 subjects in the Zemaira treatment group, 7 subjects (23%) had a total of 11 exacerbations of their COPD.

In the RAPID study 25 serious exacerbations of COPD were reported in 15 Zemaira subjects vs. 17 such events in 9 placebo subjects, corresponding to rates of 0.146 exacerbations per subject-year with Zemaira and 0.115 exacerbations per subject-year with placebo, (ratio Zemaira:Placebo [95% confidence interval]: 1.256 [0.457 - 3.454]).

Subjects who were randomized to Zemaira in the 2-year RAPID trial who then entered and received open-label Zemaira in the 2 year RAPID extension trial were in the "Early Start" group. Subjects who were randomized to Placebo in the 2-year RAPID trial who then entered and received open-label Zemaira in the 2 year RAPID extension trial were in the "Delayed Start" group. During the RAPID Extension trial 37 serious exacerbations of COPD were reported in 19 subjects (25%) in the Early Start group, corresponding to rates of 0.25 exacerbations per subject-year. In comparison, 20 serious exacerbations were reported in 11 subjects (17%) in the Delayed Start group corresponding to rates of 0.16 exacerbations per subject-year (ratio Early: Delayed [95% confidence interval]: 1.58 [0.68 – 3.66], Table 3). Among the Early Start subjects who entered the RAPID extension trial (N = 76), the exposure adjusted incidence rate of serious exacerbations during the RAPID extension trial (years 3-4) was 0.25 compared to 0.12 for those subjects during the earlier RAPID trial (years 1-2), (ratio RAPID Extension:RAPID: 2.10 [95% confidence interval: 1.21 – 3.67]). Among the Delayed Start subjects who entered the RAPID extension trial (N = 64), the exposure adjusted incidence rate of serious exacerbations during the RAPID extension trial (years 3-4) was 0.16 compared to 0.10 for those subjects during the earlier RAPID trial (years 1-2), (ratio RAPID Extension:RAPID: 1.56 [95% confidence interval: 0.80 – 3.03]).

Table 3: Comparison of Exposure-Adjusted Incidence Rates for Serious COPD Exacerbations Occurring in the RAPID study between Zemaira and Placebo subjects and in the RAPID Extension Studies between Early Start and Delayed Start subjects

Serious COPD Exacerbations*	Episode	n	%	EAIR (95% CI)	Episode	n	%	EAIR 95% CI	Treatment Ratio for EIAR (95% CI)*
N = total number of safety subjects, n = number of subjects within a category, % = (n/N)*100, CI = Confidence Interval.
Subject time at risk: Zemaira = 171.14 years, Placebo = 147.75 years, Early Start Group = 146.46 years, Delay Start Group = 124.71 years.
EAIR = Exposure-Adjusted Incidence Rate (events/subject time at risk). The point estimates and confidence intervals for EAIR values were calculated using negative binomial models.
Serious exacerbation events that overlap or occur within 1 da 以下是“全球医药”详细资料

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