CUVITRU: Package Insert and Label Information (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of CUVITRU or its effects on fertility.

13.2 Animal Toxicology and/or Pharmacology

Animal studies were conducted to evaluate possible toxicity of CUVITRU.

In a local tolerance study in mini-pigs, 50 mL of CUVITRU were administered subcutaneously to anesthetized mini-pigs. Subcutaneous administration of CUVITRU was well tolerated in this study.

In local tolerance studies in rabbits, mild to moderate inflammatory reactions were observed locally after subcutaneous administration of 2.5 mL/kg of CUVITRU. These reactions are considered to be a consequence of the animals’ immune response to the human IgG preparation and thus model specific and of minor relevance for the assessment of clinical local tolerability.

14 CLINICAL STUDIES

North America Study

A prospective, open-label, non-controlled, multi-center clinical study was conducted in North America to determine the efficacy, tolerability and PK of CUVITRU in 77 adult and pediatric subjects with PI. Efficacy was determined in 53 adults aged 16 years or older, 6 adolescents aged 12 to <16 years, and 15 children aged 2 to <12 years. CUVITRU was administered to 74 subjects with a mean dose of 222 mg/kg/week ± 71 mg/kg/week for a median treatment duration of 380.5 days (range: 30 — 629 days) and a mean (± SD) of 413.1 ± 116.5 days. The median duration of treatment did not vary significantly between age groups. The total exposure to CUVITRU was 83.70 subject-years and 4327 infusions.

Initially subjects received immune globulin 10% intravenously (IGIV) every 3 or 4 weeks at a monthly dose equivalent to that received prior to the study for 13 weeks. The objective of part 1 of the study was to determine AUCIV of total IgG following IGIV administration. In part 2 of the study, subjects received CUVITRU subcutaneously at an adjusted dose of 145% of the IGIV dose. The objective of part 2 was to determine AUCSC of total IgG following weekly CUVITRU administration and to calculate an adjusted dose to be used in part 3. The dose adjustment factor was assesed to be 145% of the IGIV 10% dose by comparing the AUCSC with the AUCIV , 0-τ (standardized to 1 week) of part 1 for the first 15 subjects that completed part 2. Subjects who completed part 1 after this assessment was available, went directly into part 3. In part 3 of the study, subjects were treated weekly for 12 weeks at the adjusted dose. The ratio of serum IgG trough levels for part 1 and 3 were compared to the expected trough level determined in part 2 to establish the individually adapted dose for part 4 for each subject. In part 4 of the study, subjects were infused weekly with CUVITRU at the individually adapted dose for 40 weeks. During part 4, an additional pharmacokinetic assessment was performed. Follow-up with the subject either by diary system or by investigator occurred 3-5 days after every infusion in each study part to document adverse events. Adverse events were assessed using the subject’s eDiary – all subjects received eDiary tablet to continuously record home treatments, adverse events, and additional information as they occurred.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 78-year old subject who had specific antibody deficiency and allergic bronchopulmonary aspergillosis while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.012 (upper limit of 99% CI: 0.024) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects during subcutaneous treatment with CUVITRU is summarized in Table 10.

Table 10 Summary of Infections and Associated Events
Parameters Results
Number of subjectsTotal number of subject-years on treatmentAnnual rate of any infections (per subject-year) 7483.702.41 (95% CI: 1.89 to 3.03)
Days on antibiotics (rate per subject-year) 57.59 (95% CI: 40.71 to 78.59)
Days off work/school/unable to perform normal daily activities due to illness or infection (rate per subject-year) 1.16 (95% CI: 0.70 to 1.79)
Number of hospitalizations due to infections (rate per subject-year) 0.012 (95% CI: 0.006 to 0.022)
Number of days in hospital due to infections (rate per subject-year) 0.06 (95% CI: 0.03 to 0.11)

In the clinical study, across all age groups, the median maximum infusion rate was 60 mL/hr/site. This infusion rate was achieved in 57.3% (2480/4327) of completed CUVITRU infusions. CUVITRU infusion rate of 60 mL/h/site was achieved in 28.6% (6/21) of pediatric subjects (2 years to <16 years of age), in 88.7% (47/53) of adults (16 years of age and older) and in 71.6% (53/74) of all subject. For more than half of CUVITRU infusions (2393/4327), a volume of 30 to 39 mL (1096/4327 infusions) or 40 to 49 mL (1297/4327 infusions) was infused per site. For 320/4327of CUVITRU infusions, a volume of 60 mL/site or more was infused. Infusion paramenters resulted in a median of 2 infusion sites (range: 1 to 4) per CUVITRU administration. During CUVITRU treatment, 84.9% (3662/4314) of infusions were administered using 1 infusion site (18.5%; 798/4314) or 2 infusion sites (66.4%; 2864/4314) across all ages. The median duration of infusions was less than 1 hour (0.95 h; range: 0.2-6.4 hours). During all treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. Infusion characteristics did not significantly differ between adult and pediatric subjects.

Throughout the study, health-related quality of life was assessed using the Pediatric Quality of Life Inventory™ (PEDS-QL) questionnaire14 (pediatric subjects) or the self-administered SF-36 survey15 (adult subjects). Quality of life was analyzed separately for the age groups 2 to 4 and 5 to 7 years (PEDS-QL, observer: parent), 8 to 12 and 13 years (PEDS-QL, observer: subject) and 14 years and older (SF-36, observer: subject). Treatment satisfaction was measured using the Life Quality Index questionnaire (LQI)16,17 and the Treatment Satisfaction Questionnaire for Medication (TSQM-9)18. The LQI was assessed for the age group 2 years to 12 years (observer: parent) and the age group 13 years and older (observer: subject) in three domains: Treatment Interference, Therapy-related Problems and Therapy Settings. The TSQM-9 was assessed in subjects aged 2 to 12 years (observer: parent) and 13 years and older (observer: subject) in 3 domains: Effectiveness, Convenience and Global Satisfaction. Differences between scores during the intravenous study part and subcutaneous 20% study part were calculated for selected domains of the instruments, see Table 11.

Table 11 Selected Patient Reported Outcomes: Differences Between the Intravenous and Subcutaneous Treatment
Scale Difference p-value
SF-36 Physical Component Score 0.89 0.067
SF-36 Mental Component Score 1.31 0.976
Total Score (PedsQL) 1.09 0.449
Treatment Interference (LQI) 1.50 0.008
Convenience (TSQM-9) 11.11 <0.001

European Study

A prospective, open-label, non-controlled, multi-center study conducted in 16 sites in Europe to evaluate the efficacy, safety, tolerability, and PK parameters of CUVITRU in subjects with PI aged 2 years and older at time of screening. The study consisted of 2 parts. In study part 1, subjects were treated with IGSC 16% for 12 weeks or with IGIV 10% for 13 weeks. Administration, dosage frequency, and dose were dependent on the pre-study treatment. However, the dose range had to be within 0.3-1.0 g/kg BW/4 weeks.

During study part 2, subjects received weekly CUVITRU infusions for 51 weeks at the dose used during study part 1, adjusted to a weekly equivalent dose if necessary. PK assessments were performed before the end of study part 1 and after approximately 5 months in study part 2 in subjects aged ≥12 years. For younger subjects (aged 2 to <12 years) only IgG trough levels were assessed to avoid multiple blood draws. The geometric mean of CUVITRU trough levels was 827 mg/dL [95% CI: 748-913]. Human and population PK parameters for CUVITRU were calculated from levels of Immunoglobulin G (IgG) measured during each part of the study.

CUVITRU was administered at the same weekly-equivalent dose as with the previously used IG product (mean (± SD) dose: 0.125 ± 0.042 g/kg/week). CUVITRU administered at this dose was shown to be effective in PI subjects aged ≥2 years.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 12-year old subject with a more severe form of hypogammaglobulinemia (XLA) while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.022 (upper limit of 99% CI: 0.049) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year, (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects in the EU study during subcutaneous treatment with CUVITRU are summarized in Table 12.

Table 12 Summary of Infections and Associated Events
Parameters Results
*
Rate = number of infections divided by the total number of subject-years under treatment
Number of subjectsAnnual rate * of any infections (rate per subject-year) 484.38 (95% CI: 3.38 to 5.56)
Days on antibiotics (rate per subject-year) 18.11 (95% CI: 13.01 to 24.41)
Days off work/school/unable to perform normal daily activities due to illness or infection (rate per subject-year) 15.55 (95% CI: 10.06 to 22.75)
Number of hospitalizations due to infections (rate per subject-year) 0.04 (95% CI: 0.02 to 0.08)
Number of days in hospital due to infections (rate per subject-year) 0.11 (95% CI: 0.05 to 0.21)

15 REFERENCES

  1. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson Jr. RP, Patel DD, Secord E, Sorenson RU, Wasserman RL, Cunningham-Rundles C, Use of Intravenous Immunoglobulin in Human Disease: A Review of Evidence by Members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol 2006; 117:S525-53.
  2. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(suppl 1):S1-63.
  3. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfusion Med Rev. 2003;17:241-251.
  4. Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013;38(4):275-84.
  5. Katz U, Sheonfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14:802-8.
  6. Ramírez E, Romero-Garrido JA, López-Granados E, Borobia AM, Pérez T, Medrano N, Rueda C, Tong HY, Herrero A, Frías J. Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective cohort study. Thromb Res. 2014 Jun;133(6):1045-51.
  7. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145.
  8. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135.
  9. Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion. 2008; 48:1598-601.
  10. Copelan EA, Strohm PL, Kennedy MS, Tuschka PJ, Hemolysis following intravenous immune globuline therapy. Transfusion 1986;26:410-412.
  11. Berg R, Shebl A, Kimber MC, Abraham M, Schreiber GB. Hemolytic events associated with intravenous immune globulin therapy: a qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012. Transfusion. 2015 Jul;55 Suppl 2:S36-46.
  12. Kahwaji J, et al.; Acute hemolysis after High-Dose Intravenous Immunoglobin Therapy in Highly HLA Sensitized Patients. Clin J Am Soc Nephrol; 2009 (4):1993-97.
  13. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion 2003;43:1023-1028.
  14. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med.Care 1999;37:126-139.
  15. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med.Care 1992;30:473-483.
  16. Daly PB, Evans JH, Kobayashi RH et al. Home-based immunoglobulin infusion therapy: quality of life and patient health perceptions. Ann.Allergy 1991;67:504-510.
  17. Nicolay U, Haag S, Eichmann F et al. Measuring treatment satisfaction in patients with primary immunodeficiency diseases receiving lifelong immunoglobulin replacement therapy. Qual.Life Res. 2005;14:1683-1691.
  18. Bharmal M, Payne K, Atkinson MJ et al. Validation of an abbreviated treatment satisfaction questionnaire for medication (TSQM-9) among patients on antihypertensive medications. Health Qual.Life Outcomes 2009;7:36.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

CUVITRU is supplied in single-dose vials containing the labeled amount of functionally active IgG. The components used in the packaging for CUVITRU are not made with natural rubber latex.

The following presentations of CUVITRU are available:

NDC Number Volume Grams Protein
0944-2850-01 5 mL 1.0
0944-2850-03 10 mL 2.0
0944-2850-05 20 mL 4.0
0944-2850-07 40 mL 8.0
0944-2850-09 50 mL 10.0

Storage and Handling

  • Store at refrigeration temperature: 2°C to 8°C [36°F to 46°F] for up to 36 months or
  • Room temperature: not to exceed 25°C [77°F]) for up to 24 months.
  • Do not return CUVITRU to the refrigerator if you take it out to room temperature.
  • Do not freeze.
  • Do not shake.
  • Keep the vials in the carton in order to protect from light.
  • Discard any unused product.
  • Do not use past the expiration date.

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