WARNING
THROMBOSIS
THROMBOSIS MAY OCCUR WITH IMMUNE GLOBULIN PRODUCTS, INCLUDING HYQVIA. RISK FACTORS MAY INCLUDE ADVANCED AGE, PROLONGED IMMOBILIZATION, HYPERCOAGULABLE CONDITIONS, HISTORY OF VENOUS OR ARTERIAL THROMBOSIS, USE OF ESTROGENS, INDWELLING VASCULAR CATHETERS, HYPERVISCOSITY AND CARDIOVASCULAR RISK FACTORS. THROMBOSIS MAY OCCUR IN THE ABSENCE OF KNOWN RISK FACTORS.
FOR PATIENTS AT RISK OF THROMBOSIS, ADMINISTER HYQVIA AT THE MINIMUM DOSE AND INFUSION RATE PRACTICABLE. ENSURE ADEQUATE HYDRATION IN PATIENTS BEFORE ADMINISTRATION.
MONITOR FOR SIGNS AND SYMPTOMS OF THROMBOSIS AND ASSESS BLOOD VISCOSITY IN PATIENTS AT RISK OF HYPERVISCOSITY.
INDICATIONS
HYQVIA IS AN IMMUNE GLOBULIN WITH A RECOMBINANT HUMAN HYALURONIDASE INDICATED FOR THE TREATMENT OF PRIMARY IMMUNODEFICIENCY (PI) IN ADULTS. THIS INCLUDES, BUT IS NOT LIMITED TO, COMMON VARIABLE IMMUNODEFICIENCY (CVID), X-LINKED AGAMMAGLOBULINEMIA, CONGENITAL AGAMMAGLOBULINEMIA, WISKOTT- ALDRICH SYNDROME, AND SEVERE COMBINED IMMUNODEFICIENCIES1,2.
LIMITATION OF USE
SAFETY AND EFFICACY OF CHRONIC USE OF RECOMBINANT HUMAN HYALURONIDASE IN HYQVIA HAVE NOT BEEN ESTABLISHED IN CONDITIONS OTHER THAN PI.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
HYQVIA IS A DUAL VIAL UNIT CONSISTING OF ONE VIAL OF A LIQUID SOLUTION CONTAINING IMMUNE GLOBULIN INFUSION 10% (HUMAN) AND ONE VIAL OF A LIQUID SOLUTION CONTAINING 160 U/ML RECOMBINANT HUMAN HYALURONIDASE.
HYQVIA IS SUPPLIED IN A DUAL VIAL UNIT OF TWO SINGLE USE VIALS CONTAINING THE LABELED AMOUNT OF FUNCTIONALLY ACTIVE IMMUNE GLOBULIN INFUSION 10% (HUMAN) AND RECOMBINANT HUMAN HYALURONIDASE. THE PACKAGING OF THIS PRODUCT IS NOT MADE WITH NATURAL RUBBER LATEX.
THE FOLLOWING PRESENTATIONS OF HYQVIA ARE AVAILABLE:
NDC NUMBER
IMMUNE GLOBULIN INFUSION 10% (HUMAN)
RECOMBINANT HUMAN HYALURONIDASE
VOLUME
GRAMS PROTEIN
VOLUME
UNITS
0944-2510- 02
25 ML
2.5
1.25 ML
200
0944-2511- 02
50 ML
5.0
2.5 ML
400
0944-2512- 02
100 ML
10.0
5.0 ML
800
0944-2513- 02
200 ML
20.0
10.0 ML
1600
0944-2514- 02
300 ML
30.0
15.0 ML
2400
STORAGE AND HANDLING
DO NOT FREEZE.
KEEP THE VIALS IN THE CARTON IN ORDER TO PROTECT FROM LIGHT.
REFRIGERATION: 2° TO 8°C [36° TO 46°F] FOR UP TO 36 MONTHS.
ROOM TEMPERATURE: UP TO 25°C [77°F] FOR UP TO 3 MONTHS DURING THE FIRST 24 MONTHS FROM THE DATE OF MANUFACTURING (MFG DATE) PRINTED ON THE CARTON.
HYQVIA MUST BE USED WITHIN 3 MONTHS AFTER REMOVAL TO ROOM TEMPERATURE BUT WITHIN THE EXPIRATION DATE ON THE CARTON AND VIAL LABEL.
DO NOT RETURN HYQVIA TO THE REFRIGERATOR AFTER IT HAS BEEN STORED AT ROOM TEMPERATURE.
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.
BAXTER HEALTHCARE CORPORATION, WESTLAKE VILLAGE, CA 91362 USA. REVISED: SEPTEMBER 2014
SIDE EFFECTS
COMMON ADVERSE REACTIONS OBSERVED IN CLINICAL TRIALS IN > 5% OF SUBJECTS WERE: LOCAL REACTIONS, HEADACHE, ANTIBODY FORMATION AGAINST RECOMBINANT HUMAN HYALURONIDASE (RHUPH20), FATIGUE, NAUSEA, PYREXIA, AND VOMITING.
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL STUDIES ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN CLINICAL STUDIES OF A PRODUCT CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL STUDIES OF ANOTHER PRODUCT AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
IMMUNE GLOBULIN INFUSION 10% (HUMAN) ADMINISTERED INTRAVENOUSLY: PRIOR TO INITIATION OF TREATMENT WITH HYQVIA, 87 PATIENTS RECEIVED 365 INFUSIONS OF IMMUNE GLOBULIN INFUSION 10% (HUMAN) ENCOMPASSING 22.2 PATIENT-YEARS. AMONG THE 87 PATIENTS TREATED, 56 (64.4%) EXPERIENCED 1 OR MORE ADVERSE REACTIONS. AMONG THE 365 INTRAVENOUS INFUSIONS, 158 ADVERSE REACTIONS OCCURRED FOR A RATE PER INFUSION OF 0.43.
A TOTAL OF 1359 INFUSIONS OF HYQVIA WERE ADMINISTERED DURING THE TRIAL; 230 OF THESE INFUSIONS OCCURRED DURING THE RAMP-UP PERIOD AND THE OTHER 1129 OCCURRED DURING THE OBSERVATION PERIOD. DURING THE OBSERVATION PERIOD, 81 PATIENTS RECEIVED 1129 INFUSIONS OF HYQVIA, OF THOSE, 67 (82.7%) EXPERIENCED ONE OR MORE ADVERSE REACTIONS. AMONG THE 1129 HYQVIA INFUSIONS, 456 ADVERSE REACTIONS OCCURRED FOR A RATE PER INFUSION OF 0.40. SEVEN OF THESE ADVERSE REACTIONS WERE SEVERE DEFINED AS MARKED IMPAIRMENT OF FUNCTION OR CAN LEAD TO TEMPORARY INABILITY TO RESUME NORMAL LIFE PATTERN; REQUIRES PROLONGED INTERVENTION OR RESULTS IN SEQUELAE.
ADVERSE REACTIONS OCCURRING IN GREATER THAN 5% OF SUBJECTS ASSOCIATED WITH INFUSIONS OF HYQVIA VS. IMMUNE GLOBULIN INFUSION 10% (HUMAN) GIVEN INTRAVENOUSLY ARE SHOWN IN TABLE 4. THE MAJORITY OF THESE ADVERSE REACTIONS WAS MILD TO MODERATE IN SEVERITY AND DID NOT NECESSITATE DISCONTINUING THE INFUSIONS. MILD IS DEFINED AS TRANSIENT DISCOMFORT THAT RESOLVES SPONTANEOUSLY OR WITH MINIMAL INTERVENTION; MODERATE IS DEFINED AS LIMITED IMPAIRMENT OF FUNCTION AND RESOLVES SPONTANEOUSLY OR WITH MINIMAL INTERVENTION WITH NO SEQUELAE. NO SERIOUS ADVERSE REACTIONS OCCURRED DURING THE HYQVIA CLINICAL TRIALS.
TABLE 4 : ADVERSE REACTIONSA IN GREATER THAN 5% OF SUBJECTS ASSOCIATED WITH INFUSIONS OF HYQVIA VS. IMMUNE GLOBULIN INFUSION 10% (HUMAN) (IGIV) GIVEN INTRAVENOUSLY
ADVERSE REACTIONSB
HYQVIA
IGIV GIVEN INTRAVENOUSLY
NUMBER OF SUBJECTS (%)
N = 81
NUMBER OF ADVERSE REACTIONS PER INFUSION (RATEC)
N = 1129
NUMBER OF SUBJECTS (%)
N = 87
NUMBER OF ADVERSE REACTIONS PER INFUSION (RATE)
N = 365
LOCAL ARS
42 (51.9%)
234 (0.21)
4 (4.6%)
4 (0.01)
SYSTEMIC ARS
55 (67.9%)
222 (0.20)
54 (62.1%)
154 (0.42)
HEADACHE
17 (21%)
40 (0.04)
22 (25.3%)
42 (0.12)
FATIQUE
9 (11.1%)
16 (0.01)
8 (9.2%)
10 (0.03)
NAUSEA
6 (7.4%)
12 (0.01)
10 (11.5%)
10 (0.03)
PYREXIA
6 (7.4%)
11 (0.01)
6 (6.9%)
7 (0.02)
VOMITING
6 (7.4%)
11 (0.01)
5 (5.7%)
7 (0.02)
A CAUSALLY RELATED ADVERSE EVENTS AND/OR TEMPORALLY ASSOCIATED ADVERSE EVENTS OCCURRING WITHIN 72 HOURS.
B EXCLUDING INFECTIONS.
C RATE = TOTAL NUMBER OF EVENTS DIVIDED BY TOTAL NUMBER OF INFUSIONS.
SIX SUBJECTS, 2 CHILDREN AND 4 ADULTS, WITHDREW FROM THE TRIAL DURING THE EFFICACY TREATMENT PERIOD WITH HYQVIA DUE TO MILD TO MODERATE ADVERSE REACTIONS. ONE CHILD WITHDREW DUE TO LOCAL PAIN AND ONE DUE TO FEVER, VOMITING, AND HEADACHES. OF THE FOUR ADULTS, TWO WITHDREW DUE TO LOCAL PAIN AND SWELLING, ONE HAD MODERATE SWELLING THAT TRANSIENTLY EXTENDED FROM THE ABDOMINAL INFUSION SITE TO THE GENITALIA, AND ONE HAD BACK INJURY.
ANTIBODIES BINDING TO RHUPH20: A TOTAL OF 15 OUT OF 83 SUBJECTS WHO WERE TREATED WITH HYQVIA DEVELOPED AN ANTIBODY CAPABLE OF BINDING TO RECOMBINANT HUMAN HYALURONIDASE IN THE CLINICAL TRIALS. THESE ANTIBODIES WERE NOT CAPABLE OF NEUTRALIZING RECOMBINANT HUMAN HYALURONIDASE.
IN THE CLINICAL TRIAL, NO TEMPORAL ASSOCIATION BETWEEN ADVERSE REACTIONS AND THE PRESENCE OF ANTIBODIES CAPABLE OF BINDING TO THE RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA COULD BE DEMONSTRATED. THERE WAS NO INCREASE IN INCIDENCE OR SEVERITY OF ADVERSE REACTIONS IN SUBJECTS WHO DEVELOPED ANTIBODIES TO RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA. IN ALL SUBJECTS, ANTIBODY TITERS DECREASED DESPITE CONTINUED TREATMENT.
THE EFFECT OF EXPOSURE TO ANTIBODIES CAPABLE OF BINDING TO RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA FOR PERIODS LONGER THAN THIS CLINICAL TRIAL HAS NOT BEEN EVALUATED.
THE LOCAL ADVERSE REACTIONS ARE LISTED BY FREQUENCY IN TABLE 5. MILD SWELLING AROUND THE INFUSION SITE WAS PRESENT IN MOST INFUSIONS DUE TO THE LARGE VOLUMES INFUSED, BUT IN GENERAL WAS NOT CONSIDERED TO BE AN ADVERSE REACTION UNLESS IT CAUSED DISCOMFORT. AMONG THE 234 LOCAL ADVERSE REACTIONS, THREE WERE SEVERE (INFUSION SITE PAIN, INFUSION SITE SWELLING AND INFUSION SITE EDEMA THAT EXTENDED FROM THE ABDOMINAL INFUSION SITE TO THE GENITALIA); ALL WERE TRANSIENT AND RESOLVED WITHOUT SEQUELAE. MORE THAN 98% OF LOCAL REACTIONS WERE EITHER MILD (70.5%) OR MODERATE (28.2%) IN SEVERITY.
TABLE 5 : MOST FREQUENT LOCAL ADVERSE REACTIONS REPORTED IN GREATER THAN 1% OF INFUSION DURING TREATMENT WITH HYQVIA
INFUSION SITE REACTION
NUMBER AND RATE OF REACTIONS PER INFUSION
N=1129
DISCOMFORT/PAIN
122 (0.11)
ERYTHEMA
32 (0.03)
SWELLING/EDEMA
35 (0.03)
PRURITUS
22 (0.02)
RATE PER INFUSION = TOTAL NUMBER OF EVENTS DIVIDED BY TOTAL NUMBER OF INFUSIONS
DURING THE COMBINED EFFICACY AND EXTENSION TRIALS ENCOMPASSING MORE THAN 3 YEARS, THE LOCAL ADVERSE REACTION RATE WAS 2.6 PER PATIENT-YEAR. DURING THE FIRST 12 MONTH PERIOD (MONTHS 1- 12), THE RATE WAS 3.68 LOCAL ADVERSE REACTIONS PER PATIENT-YEAR. DURING THE SUBSEQUENT 12 MONTH PERIOD (MONTHS 13-24), THE RATE DECLINED TO 2.12 LOCAL ADVERSE REACTIONS PER PATIENT-YEAR. FINALLY, DURING THE THIRD 12 MONTH PERIOD (MONTHS 25-36), THE RATE FURTHER DECLINED TO 0.37 LOCAL ADVERSE REACTIONS PER PATIENT-YEAR.
SIXTY-SIX OF THE 68 SUBJECTS WHO COMPLETED THE EFFICACY CLINICAL TRIAL ENROLLED IN A PROSPECTIVE, OPEN-LABEL, MULTICENTER EXTENSION TRIAL TO ASSESS THE LONGTERM SAFETY AND TOLERABILITY OF HYQVIA. SIXTY-THREE OF 66 SUBJECTS ENROLLED RECEIVED HYQVIA AND 3 RECEIVED IGIV. OF THE 63 SUBJECTS WHO RECEIVED HYQVIA, 48 COMPLETED THE EXTENSION TRIAL. THE CUMULATIVE EXPOSURE OF HYQVIA ACROSS THE TWO TRIALS WAS 188 SUBJECT-YEARS AND 2959 INFUSIONS, AND A MAXIMUM EXPOSURE OF 188 WEEKS OR UP TO APPROXIMATELY 3.5 YEARS. THERE WERE NO CLINICALLY OBSERVABLE CHANGES IN THE SKIN OR SUBCUTANEOUS TISSUE IN EITHER THE EFFICACY OR EXTENSION CLINICAL TRIALS.
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.
POSTMARKETING EXPERIENCE OF IMMUNE GLOBULIN PRODUCTS
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED AND REPORTED DURING THE POSTMARKETING USE OF IMMUNE GLOBULIN PRODUCTS ADMINISTERED INTRAVENOUSLY:
HEMATOLOGIC LEUKOPENIA, PANCYTOPENIA
NEUROLOGICAL TRANSIENT ISCHEMIC ATTACK, TREMOR, BURNING SENSATION, CEREBRAL VASCULAR ACCIDENT, COMA, SEIZURES, LOSS OF CONSCIOUSNESS
CARDIOVASCULAR HYPOTENSION, HYPERTENSION, MYOCARDIAL INFARCTION, CHEST PAIN, CARDIAC ARREST, VASCULAR COLLAPSE
RESPIRATORY PULMONARY EDEMA, DYSPNEA, OXYGEN SATURATION DECREASED, CYANOSIS, HYPOXEMIA, BRONCHOSPASM, APNEA, ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
GASTROINTESTINAL ABDOMINAL PAIN, HEPATIC DYSFUNCTION
INTEGUMENTARY HYPERHIDROSIS, ALLERGIC DERMATITIS, BULLOUS DERMATITIS, EPIDERMOLYSIS, ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME
PSYCHIATRIC ANXIETY, INSOMNIA
MUSCULOSKELETAL BACK PAIN
GENERAL/BODY AS A WHOLE EDEMA, RIGORS
READ THE HYQVIA (IMMUNE GLOBULIN INFUSION 10% (HUMAN) RECOMBINANT HUMAN HYALURONIDASE FOR SUBCUTANEOUS ADMINISTRATION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
THE IMMUNE GLOBULIN INFUSION 10% (HUMAN) PROVIDES THE THERAPEUTIC EFFECT OF HYQVIA. THE RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA INCREASES DISPERSION AND ABSORPTION OF THE IMMUNE GLOBULIN INFUSION 10% (HUMAN). THE IMMUNE GLOBULIN INFUSION 10% (HUMAN) OF HYQVIA SUPPLIES A BROAD SPECTRUM OF OPSONIZING AND NEUTRALIZING IGG ANTIBODIES AGAINST A WIDE VARIETY OF BACTERIAL AND VIRAL AGENTS. THE IMMUNE GLOBULIN INFUSION 10% (HUMAN) ALSO CONTAINS A SPECTRUM OF ANTIBODIES CAPABLE OF INTERACTING WITH AND ALTERING THE ACTIVITY OF CELLS OF THE IMMUNE SYSTEM AS WELL AS ANTIBODIES CAPABLE OF REACTING WITH CELLS SUCH AS ERYTHROCYTES. THE ROLE OF THESE ANTIBODIES AND THE MECHANISMS OF ACTION OF IGG IN THE IMMUNE GLOBULIN INFUSION 10% (HUMAN) OF HYQVIA HAVE NOT BEEN FULLY ELUCIDATED.
HYALURONAN IS A POLYSACCHARIDE FOUND IN THE EXTRACELLULAR MATRIX OF THE CONNECTIVE TISSUE8. IT IS DEPOLYMERIZED BY THE NATURALLY OCCURRING ENZYME HYALURONIDASE. UNLIKE THE STABLE STRUCTURAL COMPONENTS OF THE INTERSTITIAL MATRIX, HYALURONAN HAS A VERY FAST TURNOVER WITH A HALF-LIFE OF APPROXIMATELY 0.5 DAYS. THE RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA INCREASES PERMEABILITY OF THE SUBCUTANEOUS TISSUE BY TEMPORARILY DEPOLYMERIZING HYALURONAN. IN THE DOSES ADMINISTERED, RECOMBINANT HUMAN HYALURONIDASE OF HYQVIA ACTS LOCALLY. THE EFFECTS OF THE HYALURONIDASE ARE REVERSIBLE AND PERMEABILITY OF THE SUBCUTANEOUS TISSUE IS RESTORED WITHIN 24 TO 48 HOURS.
PHARMACOKINETICS
THE PHARMACOKINETICS (PK) OF HYQVIA WAS EVALUATED DURING A CLINICAL TRIAL OF ADULTS WITH PI AFTER THEY ACHIEVED STEADY STATE AT THEIR 3 OR 4 WEEK DOSING INTERVAL AND UNDERWENT INDIVIDUAL DOSE ADJUSTMENT [SEE CLINICAL STUDIES]. FOR ADULTS, ADJUSTMENT OF DOSE WAS BASED ON COMPARISON OF THE RATIOS OF THE AREA UNDER THE IGG CONCENTRATION VERSUS TIME CURVE (AUC) DURING INTRAVENOUS TREATMENT VERSUS DURING HYQVIA TREATMENT.
THE AUC OF HYQVIA COMPARED TO CONVENTIONAL IGSC ADMINISTRATION WAS 20% HIGHER. THE ABSOLUTE BIOAVAILABILITY OF HYQVIA WAS 93.3% RELATIVE TO IGIV.
THE PHARMACOKINETIC PARAMETERS OF HYQVIA COMPARED TO INTRAVENOUSLY ADMINISTERED IMMUNE GLOBULIN INFUSION 10% (HUMAN) ARE SHOWN IN TABLE 7. THE MEAN IGG DOSE IN WEEKLY EQUIVALENTS WAS 147 MG/KG } 50 (RANGE 134 TO 160 MG/KG). THE SERUM IGG TROUGH LEVELS ARE COMPARABLE: MEAN SERUM IGG TROUGH WITH HYQVIA WAS 1077 MG/DL COMPARED TO 1095 MG/DL WITH INTRAVENOUSLY ADMINISTERED IMMUNE GLOBULIN INFUSION 10% (HUMAN). C MAX WAS LOWER WITH HYQVIA (1607 MG/DL) THAN WITH INTRAVENOUSLY ADMINISTERED IMMUNE GLOBULIN INFUSION 10% (HUMAN) (2248 MG/DL). TIME TO REACH MAXIMUM CONCENTRATION OF IGG FOLLOWING HYQVIA ADMINISTRATION WAS 5 (3.3-5.1) DAYS.
IN THE EXTENSION TRIAL, REDUCING THE DOSING INTERVAL FROM 4 TO 2 WEEKS RESULTED IN A MEAN INCREASE OF 13% IN SERUM IG TROUGH LEVELS.
TABLE 7 : PHARMACOKINETIC PARAMETERS OF HYQVIA COMPARED TO INTRAVENOUSLY ADMINISTERED IMMUNE GLOBULIN INFUSION 10% (HUMAN) (IGIV)
HYQVIA
IGIV
NUMBER OF SUBJECTS
60
68
IGG WEEKLY DOSE [MG/KG/WEEK]
MEAN (SD)
147 (50)
139 (55)
95% CI
134 TO 160
126 TO 153
C MAX [MG/DL]
MEAN (SD)
1607 (382)
2248 (547)
95% CI
1508 TO 1706
2116 TO 2380
IGG TROUGH LEVELS [MG/DL]A
MEAN (SD)
1077 (275)
1095 (321)
95% CI
1004 TO 1149
1017 TO 1174
AUC/WEEK [G*DAYS/L]B
MEAN (SD)
91.4 (21)
98.7 (24.3)
95% CI
85.9 TO 96.8
92.8 TO 104.5
BIOAVAILABILITVC
POINT ESTIMATE
93.3
100% (DEFINED)
90% CI
91.4 TO 95.2
N/A
CLEARANCE [ML/KG/DAY]
MEAN (SD)
1.6 (0.5)D
1.4 (0.4)
95% CI
1.5 TO 1.8
1.3 TO 1.5
TERMINAL HALF-LIFE [DAYS]
MEAN (SD)
59.3 (36.1)
41.6 (26.9)
95% CI
50 TO 68.6
35.1 TO 48.1
T MAX [DAYS]
MEDIAN
5.0
0.1
95% CI
3.3 TO 5.1
0.1 TO 0.1
A N=58 FOR HYQVIA AND N=67 FOR IGIV
B STANDARDIZED TO A 7 DAY INTERVAL
C N=58 FOR HYQVIA
D APPARENT CLEARANCE
FIGURE 1 SHOWS MEAN CONCENTRATION-TIME PLOT OF IGG IN SUBJECTS 12 YEARS AND OLDER. THE CONCENTRATION-TIME PROFILE OF HYQVIA IS SIMILAR TO THAT OF INTRAVENOUS ADMINISTRATION BUT WITHOUT THE HIGH PEAK. THE PEAK TO TROUGH VARIATION IS MORE SIMILAR TO SUBCUTANEOUS ADMINISTRATION.
FIGURE 1: PHARMACOKINETIC COMPARISON OF MEAN IGG VALUES FOR HYQVIA VS. INTRAVENOUSLY AND SUBCUTANEOUSLY ADMINISTERED IMMUNE GLOBULIN INFUSION 10% (HUMAN)*
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
DEVELOPMENTAL STUDIES IN MICE DEMONSTRATED THAT ADMINISTRATION OF RECOMBINANT HUMAN HYALURONIDASE DID NOT PRODUCE TERATOGENICITY OR SIGNS OF MATERNAL TOXICITY AT DOSES UP TO 18 MG/KG (2.2 X 106 U/KG), WHICH IS 28,800 TIMES HIGHER THAN THE TYPICAL MONTHLY HUMAN DOSE. MATERNAL DOSES OF 9 AND 18 MG/KG WERE ASSOCIATED WITH REDUCED FETAL WEIGHT AND AN INCREASED NUMBER OF FETAL RESORPTIONS. NO ADVERSE EFFECTS ON FETAL DEVELOPMENT WERE OBSERVED AT A MATERNAL DOSE OF 3 MG/KG (360,000 U/KG), WHICH IS 4800 TIMES HIGHER THAN THE TYPICAL MONTHLY HUMAN DOSE.
IN A PERI-AND POST-NATAL REPRODUCTION STUDY, FEMALE MICE WERE DOSED DAILY WITH RECOMBINANT HUMAN HYALURONIDASE FROM IMPLANTATION THROUGH LACTATION AND WEANING. THERE WERE NO ADVERSE EFFECTS ON GESTATION, PARTURITION, LACTATION AND MATERNAL BEHAVIOR OR ON THE DEVELOPMENT OF THE MALE OR FEMALE OFFSPRING OF THE TREATED FEMALE MICE IN TERMS OF SEXUAL MATURATION, LEARNING AND MEMORY OF OFFSPRING, OR THEIR ABILITY TO PRODUCE ANOTHER GENERATION OF OFFSPRING AT DOSES UP TO 9 MG/KG (1.1 X106 UNIT/KG) WHICH IS 14,400 TIMES HIGHER THAN THE TYPICAL MONTHLY HUMAN DOSE.
CLINICAL STUDIES
A PROSPECTIVE, OPEN-LABEL, NON-CONTROLLED, MULTI-CENTER TRIAL WAS CONDUCTED IN THE US TO DETERMINE THE EFFICACY, TOLERABILITY AND PHARMACOKINETICS (PK) OF HYQVIA IN SUBJECTS WITH PI. TWO COHORTS OF SUBJECTS WERE ENROLLED. THIRTYONE SUBJECTS HAD BEEN TREATED INTRAVENOUSLY FOR THREE MONTHS AND THEN SUBCUTANEOUSLY EACH WEEK AT 137% OF THE INTRAVENOUS DOSE FOR APPROXIMATELY ONE YEAR BEFORE TRANSITIONING TO THE HYQVIA TRIAL. THE REMAINING SUBJECTS ALSO WERE TREATED INTRAVENOUSLY FOR 3 MONTHS AND THEN IMMEDIATELY BEGAN TREATMENT WITH HYQVIA IN THE TRIAL.
ONE WEEK AFTER THE LAST INTRAVENOUS OR SUBCUTANEOUS INFUSION, EACH SUBJECT BEGAN SUBCUTANEOUS TREATMENT WITH HYQVIA. AFTER PLACING THE SUBCUTANEOUS NEEDLE SET, THE HYALURONIDASE OF HYQVIA WAS INFUSED THROUGH THE NEEDLE SET FOLLOWED WITHIN 10 MINUTES BY THE IMMUNE GLOBULIN OF HYQVIA AT 108% OF THE INTRAVENOUS DOSE. DOSING BEGAN WITH A 1-WEEK EQUIVALENT DOSE. ONE WEEK LATER, A 2-WEEK DOSE WAS ADMINISTERED, FOLLOWED 2 WEEKS LATER WITH A 3-WEEK DOSE. FOR THOSE SUBJECTS WHO WERE ON A 4-WEEK DOSE INTERVAL PRIOR TO ENTERING THE TRIAL, 3 WEEKS LATER THE 4-WEEK DOSE WAS ADMINISTERED. THIS RAMP-UP PERIOD ALLOWED SUBJECTS TO BECOME FAMILIAR WITH THE LARGE VOLUMES REQUIRED FOR A FULL 3- OR 4-WEEK TREATMENT. SUBSEQUENTLY, SUBJECTS CONTINUED THE 3- OR 4-WEEK DOSING FOR THE REMAINDER OF THE TRIAL. AFTER 3 DOSES AT THE FULL VOLUME, A SERUM IGG TROUGH LEVEL WAS OBTAINED FOR ALL SUBJECTS, AND USED TO INDIVIDUALLY ADAPT THE SUBCUTANEOUS DOSE OF HYQVIA TO COMPENSATE FOR INDIVIDUAL VARIATION FROM THE MEAN VALUE OF 108% [SEE PHARMACOKINETICS AND DOSAGE AND ADMINISTRATION]. ALL SUBJECTS WHO COMPLETED THE TRIAL RECEIVED A MINIMUM OF 12 INFUSIONS AT THIS INDIVIDUALLY ADAPTED DOSE. THE PERIOD AFTER THE RAMP-UP WAS CONSIDERED THE EFFICACY PERIOD AND USED FOR SAFETY AND EFFICACY ANALYSES.
OUTCOME MEASURES INCLUDED THE RATE OF INFECTIONS, ADVERSE REACTIONS, TOLERABILITY OF THE INFUSIONS OF HYQVIA, NUMBER OF INFUSION SITES PER MONTH, AND INFUSION RATE. EIGHTY-NINE SUBJECTS WERE ENROLLED, 87 TREATED INTRAVENOUSLY AND 83 TREATED WITH HYQVIA. THE MAJORITY WERE CAUCASIAN (79/87, 90.8%). MEDIAN AGE WAS 35.0 YEARS (RANGE 4 TO 78 YEARS). FORTY-FOUR OF THE SUBJECTS WERE NAIVE TO SUBCUTANEOUS TREATMENT. MEDIAN SERUM IGG TROUGH LEVELS FOR THE 6 MONTHS BEFORE ENROLLMENT WERE 1033.5 MG/DL (RANGE: 405 TO 3200 MG/DL) IN SUBCUTANEOUS-EXPERIENCED SUBJECTS AND 1000 MG/DL (RANGE: 636 TO 3200) IN THE SUBCUTANEOUS-NAIVE SUBJECTS.
THE 83 SUBJECTS RECEIVED A TOTAL OF 1359 INFUSIONS OF HYQVIA DURING THE ENTIRE TRIAL. OF THESE, 1129 WERE ADMINISTERED AFTER THE RAMP-UP WHEN THE SUBJECTS WERE ON A CONSISTENT INTERVAL OF 3 OR 4 WEEKS, WHICH WAS PREDETERMINED TO BE THE EFFICACY PERIOD FOR DATA ANALYSIS.
MEDIAN DURATION OF TREATMENT IN THE IGIV PERIOD WAS 91 DAYS (RANGE 84 TO 122 DAYS). MEDIAN DURATION OF HYQVIA TREATMENT DURING THE DOSE RAMP-UP PERIOD WAS 42 DAYS (RANGE 20 TO 49), AND DURING THE EFFICACY PERIOD WAS 366 DAYS (RANGE 42 TO 507 DAYS). NONE OF THE SUBJECTS WITHDREW DUE TO A SEVERE OR SERIOUS LOCAL OR SYSTEMIC ADVERSE REACTION [SEE CLINICAL TRIAL EXPERIENCE].
THERE WERE TWO ACUTE SERIOUS BACTERIAL INFECTIONS (ASBI); BOTH EPISODES OF PNEUMONIA TREATED AS OUTPATIENTS WITH ORAL ANTIBIOTICS, DURING THE 12-MONTH EFFICACY PERIOD AND ONE ADDITIONAL PNEUMONIA THAT REQUIRED HOSPITALIZATION DURING THE RAMP-UP. BASED ON THIS, THE ANNUALIZED RATE OF ASBI WHILE TREATED WITH HYQVIA WAS 0.025, WITH AN UPPER 99% CONFIDENCE LIMIT OF 0.046, WHICH IS SIGNIFICANTLY LESS THAN (P < 0.0001) THE RATE OF ONE INFECTION PER YEAR10.
THE OVERALL RATES OF INFECTIONS THROUGHOUT BOTH THE EFFICACY AND EXTENSION TRIALS ARE SHOWN IN TABLE 8. THE SECONDARY ENDPOINTS EVALUATED IN THE EFFICACY TRIAL WERE THE ANNUAL RATE OF ALLINFECTIONS AND OTHER EFFICACY MEASURES.
TABLE 8: SUMMARY OF INFECTIONS AND OTHER SECONDARY EFFICACY ENDPOINTS
PARAMETER
ANNUAL RATE
MEAN
95% CI
INFECTIONS PER PATIENT PER YEAR (EFFICACY TRIAL)
2.97
2.51 TO 3.47
INFECTIONS PER PATIENT PER YEAR (EFFICACY AND EXTENSION TRIALS)
2.99
2.60 TO 3.92
DAYS OFF SCHOOL/WORK
3.41
2.44 TO 4.5
DAYS ON ANTIBIOTICS
20.58
15.71 TO 26.3
UNSCHEDULED PHYSICIAN VISITS FOR INFECTIONS
4.87
3.9 TO 5.97
DAYS IN HOSPITAL DUE TO INFECTION
0.0
0.0 TO 0.12
AN OBJECTIVE OF THE TRIAL WAS TO ACHIEVE THE SAME NUMBER OR FEWER INFUSIONS WITH HYQVIA PER MONTH AS WITH INTRAVENOUS ADMINISTRATION AND SIGNIFICANTLY FEWER THAN WITH CONVENTIONAL SUBCUTANEOUS ADMINISTRATION. SUMMARY OF INFUSIONS OF INTRAVENOUS ADMINISTRATION COMPARED TO HYQVIA ADMINISTRATION IS PRESENTED IN TABLE 9.
TABLE 9: SUMMARY OF INFUSIONS
PARAMETER
INTRAVENOUS
HYQVIA
MEDIAN MONTHLY NUMBER OF INFUSION SITES
1.34
(1.2 TO 1.7)
1.09
(1.0 TO 3.5)
MEAN VOLUME PER SITE (ML)
339
(75 TO 800)
292
(91 TO 648)
DOSE PER SITE (G)
33 9
(7.5 TO.80.0)
29.2
(9.1 TO 64.8)
MEDIAN DURATION OF INDIVIDUAL INFUSIONS (HR)
2.33
(0.92 TO 6.33)
2.08
(0.83 TO 4.68)
MONTHLY MEDIAN INFUSION TIME (HR/MONTH)
3.2
2.64
MEDIAN MAXIMUM INFUSION RATE (ML/HR)
246
(60 TO 668)
300
(10 TO 300)
PERCENT (%) OF INFUSION COMPLETED WITHOUT CHANGE IN RATE, INTERRUPTION AND DISCONTINUATION
95.9
97.7
SIXTEEN OF 83 SUBJECTS (19.3%) WERE INFUSED EVERY 3 WEEKS AND 67 (80.7%) WERE INFUSED EVERY 4 WEEKS. SEVENTY-EIGHT OF 83 (94%) OF SUBJECTS ATTAINED THE SAME 3- OR 4-WEEK DOSING AS THEIR PREVIOUS IV TREATMENT. ONE DECREASED FROM 4 TO 3 WEEKS, ONE FROM 4 TO 2 WEEKS AND ONE FROM 3 TO 2 WEEKS. THE PRIMARY REASON FOR DECREASING THE INTERVAL WAS DISCOMFORT DUE TO SWELLING.
IN A SEPARATE STUDY EVALUATING SUBCUTANEOUS TREATMENT WITH IMMUNE GLOBULIN INFUSION 10% (HUMAN), A MEDIAN OF 21.43 SITES WERE REQUIRED EACH MONTH WITH A MEDIAN MONTHLY INFUSION TIME OF 5.35 HOURS.
REFERENCES
8. BOOKBINDER LH, HOFER A, HALLER MF, ZEPEDA ML, KELLER G-A, LIM JE, EDGINTON TS, SHEPARD HM, PATTON JS, FROST GI. A RECOMBINANT HUMAN ENZYME FOR ENHANCED INTERSTITIAL TRANSPORT OF THERAPEUTICS. J OF CONTROLLED RELEASE 2006;114:230-241.
10. GOLDING B. IGIV CLINICAL ENDPOINTS. PRESENTED AT: BLOOD PRODUCTS ADVISORY COMMITTEE, 65TH MEETING. 17 MARCH 2000. SILVER SPRING, MD.