INDICATIONS
NATPARA IS A PARATHYROID HORMONE INDICATED AS AN ADJUNCT TO CALCIUM AND VITAMIN D TO CONTROL HYPOCALCEMIA IN PATIENTS WITH HYPOPARATHYROIDISM.
LIMITATIONS OF USE
BECAUSE OF THE POTENTIAL RISK OF OSTEOSARCOMA, NATPARA IS RECOMMENDED ONLY FOR PATIENTS WHO CANNOT BE WELL-CONTROLLED ON CALCIUM SUPPLEMENTS AND ACTIVE FORMS OF VITAMIN D ALONE. [SEE WARNINGS AND PRECAUTIONS]
NATPARA WAS NOT STUDIED IN PATIENTS WITH HYPOPARATHYROIDISM CAUSED BY CALCIUM-SENSING RECEPTOR MUTATIONS.
NATPARA WAS NOT STUDIED IN PATIENTS WITH ACUTE POST-SURGICAL HYPOPARATHYROIDISM.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
NATPARA IS SUPPLIED AS A MULTIPLE DOSE, DUAL-CHAMBER GLASS CARTRIDGE CONTAINING A STERILE POWDER AND DILUENT IN 4 DOSAGE STRENGTHS.
FOR INJECTION: 25 MCG PER DOSE STRENGTH (0.40 MG FOR RECONSTITUTION WITH 1.13 ML)
FOR INJECTION: 50 MCG PER DOSE STRENGTH (0.80 MG FOR RECONSTITUTION WITH 1.13 ML)
FOR INJECTION: 75 MCG PER DOSE STRENGTH (1.21 MG FOR RECONSTITUTION WITH 1.13 ML)
FOR INJECTION: 100 MCG PER DOSE STRENGTH (1.61 MG FOR RECONSTITUTION WITH 1.13 ML)
NATPARA (PARATHYROID HORMONE) FOR INJECTION FOR SUBCUTANEOUS USE IS SUPPLIED AS A MEDICATION CARTRIDGE, WHICH IS COMPRISED OF A MULTIPLE DOSE, DUAL-CHAMBER GLASS CARTRIDGE CONTAINING A STERILE LYOPHILIZED POWDER AND A STERILE DILUENT, WITHIN A PLASTIC CARTRIDGE HOLDER. THE MEDICATION CARTRIDGE IS AVAILABLE IN 4 DOSAGE STRENGTHS (25, 50, 75, AND 100 MCG/DOSE). THE 25 MCG/DOSE CARTRIDGE CONTAINS 0.40 MG PARATHYROID HORMONE; THE 50 MCG/DOSE CARTRIDGE CONTAINS 0.80 MG PARATHYROID HORMONE; THE 75 MCG/DOSE CARTRIDGE CONTAINS 1.21 MG PARATHYROID HORMONE; THE 100 MCG/DOSE CARTRIDGE CONTAINS 1.61 MG PARATHYROID HORMONE.
NATPARA IS SUPPLIED IN THE FOLLOWING PACKAGES:
2 CARTRIDGES OF 25 MCG/DOSE STRENGTH (NDC 68875-0202-2)
2 CARTRIDGES OF 50 MCG/DOSE STRENGTH (NDC 68875-0203-2)
2 CARTRIDGES OF 75 MCG/DOSE STRENGTH (NDC 68875-0204-2)
2 CARTRIDGES OF 100 MCG/DOSE STRENGTH (NDC 68875-0205-2)
THE DISPOSABLE NATPARA MEDICATION CARTRIDGE IS DESIGNED FOR USE WITH A REUSABLE MIXING DEVICE FOR PRODUCT RECONSTITUTION AND A REUSABLE Q-CLIQ PEN INJECTOR FOR DRUG DELIVERY. THE Q-CLIQ PEN IS DESIGNED TO DELIVER A FIXED VOLUMETRIC DOSE OF 71.4 ?L. USING THE Q-CLIQ PEN, EACH NATPARA MEDICATION CARTRIDGE DELIVERS 14 DOSES; EACH DOSE CONTAINS 25, 50, 75, OR 100 MCG OF NATPARA DEPENDING ON THE PRODUCT DOSAGE STRENGTH.
DESIGNED FOR USE WITH 31G X 8 MM BD ULTRA-FINE™ PEN NEEDLES.
THE MIXING DEVICE, PROVIDED IN A SEPARATE CARTON, IS DESIGNED TO ENABLE RECONSTITUTION OF THE PRODUCT BEFORE THE FIRST USE OF EACH CARTRIDGE. THE MIXING DEVICE CAN BE USED TO RECONSTITUTE UP TO 6 NATPARA MEDICATION CARTRIDGES.
THE Q-CLIQ PEN, PACKAGED IN A SEPARATE CARTON, CAN BE USED FOR UP TO 2 YEARS OF DAILY TREATMENT BY REPLACING THE RECONSTITUTED CARTRIDGE EVERY TWO WEEKS (14 DAYS).
INSTRUCTIONS FOR USE OF THE MIXING DEVICE AND THE Q-CLIQ PEN ARE PROVIDED WITH THE NATPARA MEDICATION CARTRIDGES.
STORAGE AND HANDLING
PRIOR TO RECONSTITUTION, THE DUAL-CHAMBER NATPARA MEDICATION CARTRIDGE SHOULD BE STORED IN THE PACKAGE PROVIDED AT REFRIGERATED TEMPERATURE, 36 TO 46°F (2 TO 8°C). AFTER RECONSTITUTION, THE MEDICATION CARTRIDGE SHOULD BE STORED IN THE Q-CLIQ PEN UNDER REFRIGERATION AT 36 TO 46°F (2 TO 8°C). THE RECONSTITUTED PRODUCT CAN BE USED FOR UP TO 14 DAYS UNDER THESE CONDITIONS. STORE AWAY FROM HEAT AND LIGHT. AVOID EXPOSURE TO ELEVATED TEMPERATURES. DISCARD RECONSTITUTED NATPARA MEDICATION CARTRIDGES AFTER 14 DAYS.
DO NOT FREEZE OR SHAKE. DO NOT USE NATPARA IF IT HAS BEEN FROZEN OR SHAKEN.
THE MIXING DEVICE AND EMPTY Q-CLIQ PEN CAN BE STORED AT ROOM TEMPERATURE.
SAFELY DISCARD NEEDLES.
MANUFACTURED FOR: NPS PHARMACEUTICALS, INC.,550 HILLS DRIVE, BEDMINSTER, NJ 07921. FOR INFORMATION ABOUT NATPARA CONTACT: NPS PHARMACEUTICALS, INC., 550 HILLS DRIVE, BEDMINSTER, NJ 07921
DOSAGE AND ADMINISTRATION
DOSING GUIDELINES
THE DOSE OF NATPARA SHOULD BE INDIVIDUALIZED BASED ON TOTAL SERUM CALCIUM (ALBUMIN-CORRECTED) AND 24-HOUR URINARY CALCIUM EXCRETION. THE RECOMMENDED NATPARA DOSE IS THE MINIMUM DOSE REQUIRED TO PREVENT BOTH HYPOCALCEMIA AND HYPERCALCIURIA. THIS DOSE WILL GENERALLY BE THE DOSE THAT MAINTAINS TOTAL SERUM CALCIUM (ALBUMIN-CORRECTED) WITHIN THE LOWER HALF OF THE NORMAL RANGE (I.E., BETWEEN 8 AND 9 MG/DL) WITHOUT THE NEED FOR ACTIVE FORMS OF VITAMIN D AND WITH CALCIUM SUPPLEMENTATION SUFFICIENT AND INDIVIDUALIZED TO MEET THE PATIENT'S DAILY REQUIREMENTS.
DOSES OF ACTIVE FORMS OF VITAMIN D AND CALCIUM SUPPLEMENTS WILL NEED TO BE ADJUSTED WHEN USING NATPARA.
BEFORE INITIATING NATPARA AND DURING THERAPY WITH NATPARA
" CONFIRM 25-HYDROXYVITAMIN D STORES ARE SUFFICIENT. IF INSUFFICIENT, REPLACE TO SUFFICIENT LEVELS PER STANDARD OF CARE.
" CONFIRM SERUM CALCIUM IS ABOVE 7.5 MG/DL BEFORE STARTING NATPARA.
" THE GOAL OF NATPARA TREATMENT IS TO ACHIEVE SERUM CALCIUM WITHIN THE LOWER HALF OF THE NORMAL RANGE.
INITIATING NATPARA
1. INITIATE NATPARA 50 MCG ONCE DAILY AS A SUBCUTANEOUS INJECTION IN THE THIGH (ALTERNATE THIGH EVERY DAY).
2. IN PATIENTS USING ACTIVE FORMS OF VITAMIN D, DECREASE THE DOSE OF ACTIVE VITAMIN D BY 50%, IF SERUM CALCIUM IS ABOVE 7.5 MG/DL.
3. IN PATIENTS USING CALCIUM SUPPLEMENTS, MAINTAIN CALCIUM SUPPLEMENT DOSE.
4. MEASURE SERUM CALCIUM CONCENTRATION WITHIN 3 TO 7 DAYS.
5. ADJUST DOSE OF ACTIVE VITAMIN D OR CALCIUM SUPPLEMENT OR BOTH BASED ON SERUM CALCIUM VALUE AND CLINICAL ASSESSMENT (I.E., SIGNS AND SYMPTOMS OF HYPOCALCEMIA OR HYPERCALCEMIA). SUGGESTED ADJUSTMENTS TO ACTIVE VITAMIN D AND CALCIUM SUPPLEMENT BASED ON SERUM CALCIUM LEVELS ARE PROVIDED BELOW.
ADJUST FIRST ADJUST SECOND
SERUM CALCIUM ACTIVE VITAMIN D FORMS CALCIUM SUPPLEMENT
ABOVE THE UPPER LIMIT OF NORMAL (10.6 MG/DL) DECREASE OR DISCONTINUE* DECREASE
GREATER THAN 9 MG/DL AND BELOW THE UPPER LIMIT OF NORMAL (10.6 MG/DL) DECREASE OR DISCONTINUE* NO CHANGE OR DECREASE IF ACTIVE VITAMIN D HAS BEEN DISCONTINUED
LESS THAN OR EAUAL TO 9 MS/DL AND ABOVE 8 MG/DL NO CHANGE NO CHANGE
LOWER THAN 8 MG/DL INCREASE INCREASE
*DISCONTINUE IN PATIENTS RECEIVING THE LOWEST AVAILABLE DOSE
6. REPEAT STEPS 4 AND 5 UNTIL TARGET SERUM CALCIUM LEVELS ARE WITHIN THE LOWER HALF OF THE NORMAL RANGE, ACTIVE VITAMIN D HAS BEEN DISCONTINUED AND CALCIUM SUPPLEMENTATION IS SUFFICIENT TO MEET DAILY REQUIREMENTS.
NATPARA DOSE ADJUSTMENTS
THE DOSE OF NATPARA MAY BE INCREASED IN INCREMENTS OF 25 MCG EVERY FOUR WEEKS UP TO A MAXIMUM DAILY DOSE OF 100 MCG IF SERUM CALCIUM CANNOT BE MAINTAINED ABOVE 8 MG/DL WITHOUT AN ACTIVE FORM OF VITAMIN D AND/OR ORAL CALCIUM SUPPLEMENTATION.
THE DOSE OF NATPARA MAY BE DECREASED TO AS LOW AS 25 MCG PER DAY IF TOTAL SERUM CALCIUM IS REPEATEDLY ABOVE 9 MG/DL AFTER THE ACTIVE FORM OF VITAMIN D HAS BEEN DISCONTINUED AND CALCIUM SUPPLEMENT HAS BEEN DECREASED TO A DOSE SUFFICIENT TO MEET DAILY REQUIREMENTS.
AFTER A NATPARA DOSE CHANGE MONITOR CLINICAL RESPONSE AS WELL AS SERUM CALCIUM. ADJUST ACTIVE VITAMIN D AND CALCIUM SUPPLEMENTS PER STEPS 4-6 ABOVE IF INDICATED [SEE INITIATING NATPARA].
NATPARA MAINTENANCE DOSE
THE MAINTENANCE DOSE SHOULD BE THE LOWEST DOSE THAT ACHIEVES A TOTAL SERUM CALCIUM (ALBUMIN-CORRECTED) WITHIN THE LOWER HALF OF THE NORMAL TOTAL SERUM CALCIUM RANGE (I.E., APPROXIMATELY 8 AND 9 MG/DL), WITHOUT THE NEED FOR ACTIVE FORMS OF VITAMIN D AND WITH CALCIUM SUPPLEMENTATION SUFFICIENT TO MEET DAILY REQUIREMENTS. MONITOR SERUM CALCIUM AND 24-HOUR URINARY CALCIUM PER STANDARD OF CARE ONCE A MAINTENANCE DOSE IS ACHIEVED.
NATPARA DOSE INTERRUPTION OR DISCONTINUATION
ABRUPT INTERRUPTION OR DISCONTINUATION OF NATPARA CAN RESULT IN SEVERE HYPOCALCEMIA. RESUME TREATMENT WITH, OR INCREASE THE DOSE OF, AN ACTIVE FORM OF VITAMIN D AND CALCIUM SUPPLEMENTS IF INDICATED IN PATIENTS INTERRUPTING OR DISCONTINUING NATPARA, MONITOR FOR SIGNS AND SYMPTOMS OF HYPOCALCEMIA AND SERUM CALCIUM LEVELS [SEE WARNINGS AND PRECAUTIONS].
IN THE CASE OF A MISSED DOSE, THE NEXT NATPARA DOSE SHOULD BE ADMINISTERED AS SOON AS REASONABLY FEASIBLE AND ADDITIONAL EXOGENOUS CALCIUM SHOULD BE TAKEN IN THE EVENT OF HYPOCALCEMIA.
RECONSTITUTION AND ADMINISTRATION INSTRUCTIONS
" PATIENTS AND CAREGIVERS WHO WILL ADMINISTER NATPARA SHOULD RECEIVE APPROPRIATE TRAINING AND INSTRUCTION BY A TRAINED HEALTHCARE PROFESSIONAL PRIOR TO FIRST USE OF NATPARA.
" FOLLOW THE INSTRUCTIONS FOR USE TO RECONSTITUTE NATPARA USING THE MIXING DEVICE FOR RECONSTITUTION AND TO ADMINISTER NATPARA USING THE PEN DELIVERY DEVICE (I.E., Q-CLIQ PEN).
" INSPECT NATPARA VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION.
" DISCARD THE NEEDLE IN A PUNCTURE-RESISTANT CONTAINER FOLLOWING ADMINISTRATION.
" STORE THE Q-CLIQ PEN CONTAINING THE REMAINING DOSES OF NATPARA IN A REFRIGERATOR.
" ALL RECONSTITUTED NATPARA MEDICATION CARTRIDGES OLDER THAN 14 DAYS MUST BE DISCARDED. [SEE HOW SUPPLIED/STORAGE AND HANDLING]
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" OSTEOSARCOMA [SEE BOXED WARNING, WARNINGS AND PRECAUTIONS]
" HYPERCALCEMIA [SEE WARNINGS AND PRECAUTIONS]
" HYPOCALCEMIA [SEE WARNINGS AND PRECAUTIONS]
ADVERSE REACTIONS IN CLINICAL TRIALS FOR HYPOPARATHYROIDISM
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
NATPARA WAS STUDIED IN A PLACEBO-CONTROLLED TRIAL [SEE CLINICAL STUDIES].
THE DATA DESCRIBED IN TABLE 1 BELOW REFLECT EXPOSURE TO NATPARA IN 84 PATIENTS, INCLUDING 78 EXPOSED FOR 24 WEEKS. THE MEAN AGE OF THE TRIAL POPULATION WAS 47 YEARS AND RANGED FROM 19 TO 74 YEARS OLD. SEVENTY-NINE PERCENT (79%) WERE FEMALES. NINETY SIX PERCENT (96%) WERE CAUCASIAN, 0.8% WERE BLACK, AND 1.6% WERE ASIAN. PATIENTS HAD HAD HYPOPARATHYROIDISM FOR ON AVERAGE 15 YEARS AND HYPOPARATHYROIDISM WAS CAUSED BY POST-SURGICAL COMPLICATIONS IN 71% OF CASES, IDIOPATHIC HYPOPARATHYROIDISM IN 25% OF CASES, DIGEORGE SYNDROME IN 3% OF CASES, AND AUTO-IMMUNE HYPOPARATHYROIDISM IN 1% OF CASES. PRIOR TO TRIAL ENROLLMENT, PARTICIPANTS WERE RECEIVING A MEDIAN (INTERQUARTILE RANGE) DAILY ORAL CALCIUM DOSE OF 2000 (1250, 3000) MG AND A MEDIAN DAILY ORAL ACTIVE VITAMIN D DOSE EQUIVALENT TO 0.75 (0.5, 1) MCG OF CALCITRIOL. THE MEAN EGFR AT BASELINE WAS 97.4 ML/MIN/1.73 M² AND 45%, 10% AND 0% HAD MILD, MODERATE AND SEVERE RENAL IMPAIRMENT, RESPECTIVELY, AT BASELINE. DURING THE TRIAL, MOST PATIENTS RECEIVED 100 MCG AND THE DOSE RANGE WAS 50 TO 100 MCG ADMINISTERED SUBCUTANEOUSLY ONCE DAILY IN THE THIGH.
TABLE 1 LISTS COMMON ADVERSE REACTIONS ASSOCIATED WITH NATPARA USE IN THE CLINICAL TRIAL. COMMON ADVERSE REACTIONS WERE REACTIONS THAT OCCURRED IN ? 5% OF SUBJECTS AND OCCURRED MORE COMMONLY ON NATPARA THAN ON PLACEBO.
TABLE 1: COMMON ADVERSE REACTIONS ASSOCIATED WITH NATPARA USE IN SUBJECTS WITH HYPOPARATHYROIDISM
ADVERSE REACTION PLACEBO
(N=40) % NATPARA
(N=84) %
PARAESTHESIA 25 31
HYPOCALCEMIA* 23 27
HEADACHE 23 25
HYPERCALCEMIA* 3 19
NAUSEA 18 18
HYPOAESTHESIA 10 14
DIARRHEA 3 12
VOMITING 0 12
ARTHRALGIA 10 11
HYPERCALCIURIA* 8 11
PAIN IN EXTREMITY 8 10
UPPER RESPIRATORY TRACT INFECTION 5 8
ABDOMINAL PAIN UPPER 3 7
SINUSITIS 5 7
BLOOD 25-HYDROXYCHOLECALCIFEROL DECREASED 3 6
HYPERTENSION 5 6
HYPOAESTHESIA FACIAL 3 6
NECK PAIN 3 6
* HYPOCALCEMIA COMBINES REPORTED EVENTS OF HYPOCALCEMIA AND BLOOD CALCIUM DECREASED' HYPERCALCIURIA COMBINES REPORTED EVENTS OF HYPERCALCIURIA AND URINE CALCIUM INCREASED, AND HYPERCALCEMIA COMBINES REPORTED EVENTS OF HYPERCALCEMIA AND BLOOD CALCIUM INCREASED.
HYPERCALCEMIA
IN THE OVERALL PIVOTAL TRIAL A GREATER PROPORTION OF PATIENTS ON NATPARA HAD ALBUMIN-CORRECTED SERUM CALCIUM ABOVE THE NORMAL RANGE (8.4 TO 10.6 MG/DL). DURING THE ENTIRE TRIAL DURATION 3 PATIENTS ON NATPARA AND 1 PATIENT ON PLACEBO HAD A CALCIUM LEVEL ABOVE 12 MG/DL. TABLE 2 DISPLAYS THE NUMBER OF SUBJECTS WHO HAD ALBUMIN-CORRECTED SERUM CALCIUM LEVELS ABOVE THE NORMAL RANGE (8.4 TO 10.6 MG/DL) BY STUDY TREATMENT PERIOD IN THE PLACEBO-CONTROLLED STUDY BASED ON ROUTINE MONITORING AT EACH TRIAL VISIT. MORE PATIENTS RANDOMIZED TO NATPARA HAD HYPERCALCEMIA IN BOTH PHASES OF THE STUDY (NOTE: ALL TRIAL PARTICIPANTS UNDERWENT A 50% REDUCTION IN ACTIVE VITAMIN D DOSE AT RANDOMIZATION).
TABLE 2: PROPORTION OF SUBJECTS WITH ALBUMIN-CORRECTED SERUM CALCIUM GREATER THAN UPPER LIMIT OF NORMAL (10.6 MG/DL) DURING THE TREATMENT PERIOD
ALBUMIN-CORRECTED SERUM CALCIUM TITRATION PERIOD
(WEEKS 0-12)* MAINTENANCE PERIOD
(WEEKS 12-24)
PLACEBO
N=40 NATPARA
N=84 PLACEBO
N=40 NATPARA
N=84
> 10.6 TO ? 12 MG/DL 0% 30 % 0% 10%
> 12 TO ? 13 MG/DL 0% 2% 3% 0%
*NATPARA WAS ONLY TITRATED UPWARDS FOR UP TO WEEK 6
HYPOCALCEMIA
TABLE 3 DISPLAYS THE NUMBER OF SUBJECTS WHO HAD ALBUMIN-CORRECTED SERUM CALCIUM LEVELS BELOW 8.4 MG/DL BY TREATMENT PERIOD IN THE PLACEBO-CONTROLLED STUDY BASED ON ROUTINE MONITORING AT EACH TRIAL VISIT. MORE PATIENTS RANDOMIZED TO PLACEBO HAD HYPOCALCEMIA OF LESS THAN 7 MG/DL IN THE TITRATION PHASE (NOTE: ALL TRIAL PARTICIPANTS UNDERWENT A 50% REDUCTION IN ACTIVE VITAMIN D DOSE AT RANDOMIZATION). MORE PATIENTS RANDOMIZED TO NATPARA HAD HYPOCALCEMIA OF LESS THAN 7 MG/DL IN THE DOSE MAINTENANCE PHASE.
TABLE 3 : PROPORTION OF SUBJECTS WITH ALBUMIN-CORRECTED SERUM CALCIUM BELOW THE LOWER LIMIT OF NORMAL (8.4 MG/DL) DURING THE TREATMENT PERIOD
TITRATION PERIOD(WEEKS 0-12) MAINTENANCE PERIOD(WEEKS 12-24)
PLACEBO
N=40 NATPARA
N=84 PLACEBO
N=40 NATPARA
N=84
ALBUMIN-CORRECTED SERUM CALCIUM
? 7 TO < 8.4 MG/DL 98% 79% 75% 71%
< 7 MG/DL 18% 6% 0% 12%
THE RISK OF HYPOCALCEMIA INCREASES WHEN NATPARA IS WITHDRAWN. AT THE END OF THE TRIAL, NATPARA AND PLACEBO WERE WITHDRAWN, CALCIUM AND ACTIVE VITAMIN D WERE RETURNED TO BASELINE DOSES AND SUBJECTS WERE FOLLOWED FOR 4 WEEKS. DURING THIS WITHDRAWAL PHASE, MORE PATIENTS PREVIOUSLY RANDOMIZED TO NATPARA EXPERIENCED AN ALBUMIN-CORRECTED SERUM CALCIUM VALUE OF LESS THAN 7 MG/DL (5.0% VERSUS 17% FOR PREVIOUS TREATMENT WITH PLACEBO AND NATPARA RESPECTIVELY). TWENTY SUBJECTS (24%) PREVIOUSLY RANDOMIZED TO NATPARA EXPERIENCED ADVERSE REACTIONS OF HYPOCALCEMIA IN THE POST-TREATMENT PHASE COMPARED TO THREE SUBJECTS (8%) PREVIOUSLY RANDOMIZED TO PLACEBO. FIVE SUBJECTS PREVIOUSLY RANDOMIZED TO NATPARA WITH ALBUMIN-CORRECTED SERUM CALCIUM BELOW 7 MG/DL REQUIRED TREATMENT WITH IV CALCIUM GLUCONATE TO CORRECT HYPOCALCEMIA.
HYPERCALCIURIA
TREATMENT WITH NATPARA DID NOT LOWER 24 HOUR URINARY CALCIUM EXCRETION IN THE PLACEBO-CONTROLLED TRIAL. THE PROPORTION OF SUBJECTS WITH HYPERCALCIURIA (DEFINED AS A URINE CALCIUM LEVELS OF > 300 MG/24 HOURS) WAS SIMILAR AT BASELINE AND TRIAL END IN THE NATPARA AND PLACEBO GROUPS. THE MEDIAN (IQR) 24-HOUR URINE CALCIUM AT TRIAL END WAS SIMILAR BETWEEN NATPARA [231 (168-351) MG/24 HOURS], AND PLACEBO [232 (139-342) MG/24 HOURS]. AT TRIAL END, SERUM CALCIUM VALUES BETWEEN NATPARA AND PLACEBO WERE ALSO SIMILAR. RISK OF HYPERCALCIURIA THROUGHOUT THE TRIAL WAS RELATED TO SERUM CALCIUM LEVELS. TO MINIMIZE THE RISK OF HYPERCALCIURIA, NATPARA SHOULD BE DOSED TO A TARGET ALBUMIN-CORRECTED TOTAL SERUM CALCIUM WITHIN THE LOWER HALF OF THE NORMAL RANGE (I.E., BETWEEN 8 AND 9 MG/DL) [SEE DOSAGE AND ADMINISTRATION].
IMMUNOGENICITY
NATPARA MAY TRIGGER THE DEVELOPMENT OF ANTIBODIES. IN THE PLACEBO-CONTROLLED STUDY IN ADULTS WITH HYPOPARATHYROIDISM, THE INCIDENCE OF ANTI-PTH ANTIBODIES WAS 8.6% (3/35) AND 5.9% (1/17) IN SUBJECTS WHO RECEIVED SUBCUTANEOUS ADMINISTRATION OF 50 TO 100 MCG NATPARA OR PLACEBO ONCE DAILY FOR 24 WEEKS, RESPECTIVELY.
ACROSS ALL CLINICAL STUDIES IN SUBJECTS WITH HYPOPARATHYROIDISM FOLLOWING TREATMENT WITH NATPARA FOR UP TO 2.6 YEARS, THE IMMUNOGENICITY INCIDENCE RATE WAS 16.1% (14/87). THESE 14 SUBJECTS HAD LOW TITER ANTI-PTH ANTIBODIES AND OF THESE, 3 SUBJECTS SUBSEQUENTLY BECAME ANTIBODY NEGATIVE. ONE OF THESE SUBJECTS HAD ANTIBODIES WITH NEUTRALIZING ACTIVITY; THIS SUBJECT MAINTAINED A CLINICAL RESPONSE WITH NO EVIDENCE OF IMMUNE-RELATED ADVERSE REACTIONS. ANTI-PTH ANTIBODIES DID NOT APPEAR TO AFFECT EFFICACY OR SAFETY DURING THE CLINICAL TRIALS BUT THEIR LONGER-TERM IMPACT IS UNKNOWN.
IMMUNOGENICITY ASSAY RESULTS ARE HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY AND MAY BE INFLUENCED BY SEVERAL FACTORS SUCH AS: ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATION, AND UNDERLYING DISEASES. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO NATPARA WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
READ THE NATPARA (PARATHYROID HORMONE FOR INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" OSTEOSARCOMA [SEE BOXED WARNING, WARNINGS AND PRECAUTIONS]
" HYPERCALCEMIA [SEE WARNINGS AND PRECAUTIONS]
" HYPOCALCEMIA [SEE WARNINGS AND PRECAUTIONS]
ADVERSE REACTIONS IN CLINICAL TRIALS FOR HYPOPARATHYROIDISM
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
NATPARA WAS STUDIED IN A PLACEBO-CONTROLLED TRIAL [SEE CLINICAL STUDIES].
THE DATA DESCRIBED IN TABLE 1 BELOW REFLECT EXPOSURE TO NATPARA IN 84 PATIENTS, INCLUDING 78 EXPOSED FOR 24 WEEKS. THE MEAN AGE OF THE TRIAL POPULATION WAS 47 YEARS AND RANGED FROM 19 TO 74 YEARS OLD. SEVENTY-NINE PERCENT (79%) WERE FEMALES. NINETY SIX PERCENT (96%) WERE CAUCASIAN, 0.8% WERE BLACK, AND 1.6% WERE ASIAN. PATIENTS HAD HAD HYPOPARATHYROIDISM FOR ON AVERAGE 15 YEARS AND HYPOPARATHYROIDISM WAS CAUSED BY POST-SURGICAL COMPLICATIONS IN 71% OF CASES, IDIOPATHIC HYPOPARATHYROIDISM IN 25% OF CASES, DIGEORGE SYNDROME IN 3% OF CASES, AND AUTO-IMMUNE HYPOPARATHYROIDISM IN 1% OF CASES. PRIOR TO TRIAL ENROLLMENT, PARTICIPANTS WERE RECEIVING A MEDIAN (INTERQUARTILE RANGE) DAILY ORAL CALCIUM DOSE OF 2000 (1250, 3000) MG AND A MEDIAN DAILY ORAL ACTIVE VITAMIN D DOSE EQUIVALENT TO 0.75 (0.5, 1) MCG OF CALCITRIOL. THE MEAN EGFR AT BASELINE WAS 97.4 ML/MIN/1.73 M² AND 45%, 10% AND 0% HAD MILD, MODERATE AND SEVERE RENAL IMPAIRMENT, RESPECTIVELY, AT BASELINE. DURING THE TRIAL, MOST PATIENTS RECEIVED 100 MCG AND THE DOSE RANGE WAS 50 TO 100 MCG ADMINISTERED SUBCUTANEOUSLY ONCE DAILY IN THE THIGH.
TABLE 1 LISTS COMMON ADVERSE REACTIONS ASSOCIATED WITH NATPARA USE IN THE CLINICAL TRIAL. COMMON ADVERSE REACTIONS WERE REACTIONS THAT OCCURRED IN ? 5% OF SUBJECTS AND OCCURRED MORE COMMONLY ON NATPARA THAN ON PLACEBO.
TABLE 1: COMMON ADVERSE REACTIONS ASSOCIATED WITH NATPARA USE IN SUBJECTS WITH HYPOPARATHYROIDISM
ADVERSE REACTION PLACEBO
(N=40) % NATPARA
(N=84) %
PARAESTHESIA 25 31
HYPOCALCEMIA* 23 27
HEADACHE 23 25
HYPERCALCEMIA* 3 19
NAUSEA 18 18
HYPOAESTHESIA 10 14
DIARRHEA 3 12
VOMITING 0 12
ARTHRALGIA 10 11
HYPERCALCIURIA* 8 11
PAIN IN EXTREMITY 8 10
UPPER RESPIRATORY TRACT INFECTION 5 8
ABDOMINAL PAIN UPPER 3 7
SINUSITIS 5 7
BLOOD 25-HYDROXYCHOLECALCIFEROL DECREASED 3 6
HYPERTENSION 5 6
HYPOAESTHESIA FACIAL 3 6
NECK PAIN 3 6
* HYPOCALCEMIA COMBINES REPORTED EVENTS OF HYPOCALCEMIA AND BLOOD CALCIUM DECREASED' HYPERCALCIURIA COMBINES REPORTED EVENTS OF HYPERCALCIURIA AND URINE CALCIUM INCREASED, AND HYPERCALCEMIA COMBINES REPORTED EVENTS OF HYPERCALCEMIA AND BLOOD CALCIUM INCREASED.
HYPERCALCEMIA
IN THE OVERALL PIVOTAL TRIAL A GREATER PROPORTION OF PATIENTS ON NATPARA HAD ALBUMIN-CORRECTED SERUM CALCIUM ABOVE THE NORMAL RANGE (8.4 TO 10.6 MG/DL). DURING THE ENTIRE TRIAL DURATION 3 PATIENTS ON NATPARA AND 1 PATIENT ON PLACEBO HAD A CALCIUM LEVEL ABOVE 12 MG/DL. TABLE 2 DISPLAYS THE NUMBER OF SUBJECTS WHO HAD ALBUMIN-CORRECTED SERUM CALCIUM LEVELS ABOVE THE NORMAL RANGE (8.4 TO 10.6 MG/DL) BY STUDY TREATMENT PERIOD IN THE PLACEBO-CONTROLLED STUDY BASED ON ROUTINE MONITORING AT EACH TRIAL VISIT. MORE PATIENTS RANDOMIZED TO NATPARA HAD HYPERCALCEMIA IN BOTH PHASES OF THE STUDY (NOTE: ALL TRIAL PARTICIPANTS UNDERWENT A 50% REDUCTION IN ACTIVE VITAMIN D DOSE AT RANDOMIZATION).
TABLE 2: PROPORTION OF SUBJECTS WITH ALBUMIN-CORRECTED SERUM CALCIUM GREATER THAN UPPER LIMIT OF NORMAL (10.6 MG/DL) DURING THE TREATMENT PERIOD
ALBUMIN-CORRECTED SERUM CALCIUM TITRATION PERIOD
(WEEKS 0-12)* MAINTENANCE PERIOD
(WEEKS 12-24)
PLACEBO
N=40 NATPARA
N=84 PLACEBO
N=40 NATPARA
N=84
> 10.6 TO ? 12 MG/DL 0% 30 % 0% 10%
> 12 TO ? 13 MG/DL 0% 2% 3% 0%
*NATPARA WAS ONLY TITRATED UPWARDS FOR UP TO WEEK 6
HYPOCALCEMIA
TABLE 3 DISPLAYS THE NUMBER OF SUBJECTS WHO HAD ALBUMIN-CORRECTED SERUM CALCIUM LEVELS BELOW 8.4 MG/DL BY TREATMENT PERIOD IN THE PLACEBO-CONTROLLED STUDY BASED ON ROUTINE MONITORING AT EACH TRIAL VISIT. MORE PATIENTS RANDOMIZED TO PLACEBO HAD HYPOCALCEMIA OF LESS THAN 7 MG/DL IN THE TITRATION PHASE (NOTE: ALL TRIAL PARTICIPANTS UNDERWENT A 50% REDUCTION IN ACTIVE VITAMIN D DOSE AT RANDOMIZATION). MORE PATIENTS RANDOMIZED TO NATPARA HAD HYPOCALCEMIA OF LESS THAN 7 MG/DL IN THE DOSE MAINTENANCE PHASE.
TABLE 3 : PROPORTION OF SUBJECTS WITH ALBUMIN-CORRECTED SERUM CALCIUM BELOW THE LOWER LIMIT OF NORMAL (8.4 MG/DL) DURING THE TREATMENT PERIOD
TITRATION PERIOD(WEEKS 0-12) MAINTENANCE PERIOD(WEEKS 12-24)
PLACEBO
N=40 NATPARA
N=84 PLACEBO
N=40 NATPARA
N=84
ALBUMIN-CORRECTED SERUM CALCIUM
? 7 TO < 8.4 MG/DL 98% 79% 75% 71%
< 7 MG/DL 18% 6% 0% 12%
THE RISK OF HYPOCALCEMIA INCREASES WHEN NATPARA IS WITHDRAWN. AT THE END OF THE TRIAL, NATPARA AND PLACEBO WERE WITHDRAWN, CALCIUM AND ACTIVE VITAMIN D WERE RETURNED TO BASELINE DOSES AND SUBJECTS WERE FOLLOWED FOR 4 WEEKS. DURING THIS WITHDRAWAL PHASE, MORE PATIENTS PREVIOUSLY RANDOMIZED TO NATPARA EXPERIENCED AN ALBUMIN-CORRECTED SERUM CALCIUM VALUE OF LESS THAN 7 MG/DL (5.0% VERSUS 17% FOR PREVIOUS TREATMENT WITH PLACEBO AND NATPARA RESPECTIVELY). TWENTY SUBJECTS (24%) PREVIOUSLY RANDOMIZED TO NATPARA EXPERIENCED ADVERSE REACTIONS OF HYPOCALCEMIA IN THE POST-TREATMENT PHASE COMPARED TO THREE SUBJECTS (8%) PREVIOUSLY RANDOMIZED TO PLACEBO. FIVE SUBJECTS PREVIOUSLY RANDOMIZED TO NATPARA WITH ALBUMIN-CORRECTED SERUM CALCIUM BELOW 7 MG/DL REQUIRED TREATMENT WITH IV CALCIUM GLUCONATE TO CORRECT HYPOCALCEMIA.
HYPERCALCIURIA
TREATMENT WITH NATPARA DID NOT LOWER 24 HOUR URINARY CALCIUM EXCRETION IN THE PLACEBO-CONTROLLED TRIAL. THE PROPORTION OF SUBJECTS WITH HYPERCALCIURIA (DEFINED AS A URINE CALCIUM LEVELS OF > 300 MG/24 HOURS) WAS SIMILAR AT BASELINE AND TRIAL END IN THE NATPARA AND PLACEBO GROUPS. THE MEDIAN (IQR) 24-HOUR URINE CALCIUM AT TRIAL END WAS SIMILAR BETWEEN NATPARA [231 (168-351) MG/24 HOURS], AND PLACEBO [232 (139-342) MG/24 HOURS]. AT TRIAL END, SERUM CALCIUM VALUES BETWEEN NATPARA AND PLACEBO WERE ALSO SIMILAR. RISK OF HYPERCALCIURIA THROUGHOUT THE TRIAL WAS RELATED TO SERUM CALCIUM LEVELS. TO MINIMIZE THE RISK OF HYPERCALCIURIA, NATPARA SHOULD BE DOSED TO A TARGET ALBUMIN-CORRECTED TOTAL SERUM CALCIUM WITHIN THE LOWER HALF OF THE NORMAL RANGE (I.E., BETWEEN 8 AND 9 MG/DL) [SEE DOSAGE AND ADMINISTRATION].
IMMUNOGENICITY
NATPARA MAY TRIGGER THE DEVELOPMENT OF ANTIBODIES. IN THE PLACEBO-CONTROLLED STUDY IN ADULTS WITH HYPOPARATHYROIDISM, THE INCIDENCE OF ANTI-PTH ANTIBODIES WAS 8.6% (3/35) AND 5.9% (1/17) IN SUBJECTS WHO RECEIVED SUBCUTANEOUS ADMINISTRATION OF 50 TO 100 MCG NATPARA OR PLACEBO ONCE DAILY FOR 24 WEEKS, RESPECTIVELY.
ACROSS ALL CLINICAL STUDIES IN SUBJECTS WITH HYPOPARATHYROIDISM FOLLOWING TREATMENT WITH NATPARA FOR UP TO 2.6 YEARS, THE IMMUNOGENICITY INCIDENCE RATE WAS 16.1% (14/87). THESE 14 SUBJECTS HAD LOW TITER ANTI-PTH ANTIBODIES AND OF THESE, 3 SUBJECTS SUBSEQUENTLY BECAME ANTIBODY NEGATIVE. ONE OF THESE SUBJECTS HAD ANTIBODIES WITH NEUTRALIZING ACTIVITY; THIS SUBJECT MAINTAINED A CLINICAL RESPONSE WITH NO EVIDENCE OF IMMUNE-RELATED ADVERSE REACTIONS. ANTI-PTH ANTIBODIES DID NOT APPEAR TO AFFECT EFFICACY OR SAFETY DURING THE CLINICAL TRIALS BUT THEIR LONGER-TERM IMPACT IS UNKNOWN.
IMMUNOGENICITY ASSAY RESULTS ARE HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY AND MAY BE INFLUENCED BY SEVERAL FACTORS SUCH AS: ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATION, AND UNDERLYING DISEASES. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO NATPARA WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
READ THE NATPARA (PARATHYROID HORMONE FOR INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
NATPARA IS A PARATHYROID HORMONE. PARATHYROID HORMONE RAISES SERUM CALCIUM BY INCREASING RENAL TUBULAR CALCIUM REABSORPTION, INCREASING INTESTINAL CALCIUM ABSORPTION (I.E., BY CONVERTING 25 OH VITAMIN D TO 1,25 OH2 VITAMIN D) AND BY INCREASING BONE TURNOVER WHICH RELEASES CALCIUM INTO THE CIRCULATION.
PHARMACODYNAMICS
THE PHARMACODYNAMICS IN SUBJECTS WITH HYPOPARATHYROIDISM AFTER SINGLE SUBCUTANEOUS ADMINISTRATION OF 50 AND 100 MCG DOSE OF NATPARA IN THE THIGH WERE EVALUATED.
TREATMENT WITH NATPARA INCREASES SERUM CALCIUM LEVELS (FIGURE 2). THE INCREASE IN SERUM CALCIUM LEVELS IN HYPOPARATHYROIDISM SUBJECTS OCCURS IN A DOSE-RELATED MANNER. MEAN PEAK SERUM CALCIUM LEVELS ARE REACHED BETWEEN 10 AND 12 HOURS FOLLOWING A SINGLE SUBCUTANEOUS INJECTION AND THE INCREASE IN SERUM CALCIUM ABOVE BASELINE IS SUSTAINED FOR MORE THAN 24 HOURS AFTER ADMINISTRATION. THE MAXIMUM MEAN INCREASES OF SERUM CALCIUM, WHICH OCCURRED AT 12 HOURS, WERE APPROXIMATELY 0.5 MG/DL AND 0.7 MG/DL FROM BASELINE WITH THE 50 MCG AND 100 MCG DOSES, RESPECTIVELY. THE MEAN CALCIUM INTAKE FOR THE 50 AND 100 MCG DOSES WAS 1700 MG [SEE PHARMACOKINETICS].
PHARMACOKINETICS
FOLLOWING SINGLE SUBCUTANEOUS INJECTIONS OF NATPARA AT 50 MCG AND 100 MCG IN SUBJECTS WITH HYPOPARATHYROIDISM, PEAK PLASMA CONCENTRATIONS (MEAN TMAX) OF NATPARA OCCURS WITHIN 5 TO 30 MINUTES AND A SECOND USUALLY SMALLER PEAK AT 1 TO 2 HOURS. THE PLASMA AUC INCREASED IN A DOSE PROPORTIONAL MANNER FROM 50 MCG TO 100 MCG. THE APPARENT TERMINAL HALF-LIFE (T½) WAS 3.02 AND 2.83 HOURS FOR THE 50 AND 100 MCG DOSE, RESPECTIVELY.
MEAN UNADJUSTED CONCENTRATION-TIME PROFILES OF PARATHYROID HORMONE IN PLASMA FOLLOWING SC ADMINISTRATION OF 100 MCG OF NATPARA ARE PRESENTED IN FIGURE 2. ONE 100 MCG DOSE OF NATPARA PROVIDES A 24-HOUR CALCEMIC RESPONSE IN HYPOPARATHYROIDISM SUBJECTS.
FIGURE 2: MEAN (±SE) UNADJUSTED PLASMA PARATHYROID HORMONE AND ALBUMIN-CORRECTED SERUM CALCIUM CONCENTRATION FOLLOWING 100 MCG SC ADMINISTRATION IN SUBJECTS WITH HYPOPARATHYROIDISM
ABSORPTION
NATPARA ADMINISTERED SUBCUTANEOUSLY HAS AN ABSOLUTE BIOAVAILABILITY OF 53%.
DISTRIBUTION
NATPARA HAS A VOLUME OF DISTRIBUTION OF 5.35 L AT STEADY STATE.
METABOLISM
IN VITRO AND IN VIVO STUDIES DEMONSTRATED THAT THE CLEARANCE OF PARATHYROID HORMONE IS PRIMARILY A HEPATIC PROCESS WITH A LESSER ROLE PLAYED BY THE KIDNEYS.
EXCRETION
IN THE LIVER, MOST OF THE INTACT PARATHYROID HORMONE IS CLEAVED BY CATHEPSINS. IN THE KIDNEY, A SMALL AMOUNT OF PARATHYROID HORMONE BINDS TO PHYSIOLOGIC PTH-1 RECEPTORS, BUT MOST IS FILTERED AT THE GLOMERULUS. C-TERMINAL FRAGMENTS ARE ALSO CLEARED EFFICIENTLY BY GLOMERULAR FILTRATION.
HEPATIC IMPAIRMENT
A PHARMACOKINETIC STUDY WAS CONDUCTED IN 6 MEN AND 6 WOMEN WITH MODERATE HEPATIC IMPAIRMENT (CHILD-PUGH CLASSIFICATION OF 7-9 [GRADE B]) AS COMPARED WITH A MATCHED GROUP OF 12 SUBJECTS WITH NORMAL HEPATIC FUNCTION. FOLLOWING A SINGLE 100-MCG SUBCUTANEOUS DOSE, THE MEAN CMAX AND BASELINE-CORRECTED CMAX VALUES WERE 18% TO 20% GREATER IN THE MODERATELY IMPAIRED SUBJECTS THAN IN THOSE WITH NORMAL FUNCTION. THERE WERE NO APPARENT DIFFERENCES IN THE SERUM TOTAL CALCIUM CONCENTRATION-TIME PROFILES BETWEEN THE 2 HEPATIC FUNCTION GROUPS. NO DOSE ADJUSTMENT FOR NATPARA IS RECOMMENDED IN PATIENTS WITH MILD TO MODERATE HEPATIC IMPAIRMENT.
RENAL IMPAIRMENT
PHARMACOKINETICS FOLLOWING A SINGLE NATPARA 100 MCG SUBCUTANEOUS DOSE WAS EVALUATED IN 16 SUBJECTS WITH NORMAL RENAL FUNCTION (CREATININE CLEARANCE (CLCR) > 90 ML/MIN) AND 16 SUBJECTS WITH RENAL IMPAIRMENT. THE MEAN MAXIMUM CONCENTRATION (CMAX) OF PARATHYROID HORMONE FOLLOWING ADMINISTRATION OF 100 MCG NATPARA IN SUBJECTS WITH MILD (CLCR 60 TO 90 ML/MIN) AND MODERATE (CLCR 30 TO 60 ML/MIN) RENAL IMPAIRMENT WAS APPROXIMATELY 22% HIGHER THAN THAT OBSERVED IN SUBJECTS WITH NORMAL RENAL FUNCTION. EXPOSURE TO PARATHYROID HORMONE AS MEASURED BY AUC0-LAST AND BASELINE-CORRECTED AUC0-LAST WAS APPROXIMATELY 3.9% AND 2.5%, RESPECTIVELY, HIGHER THAN THAT OBSERVED FOR SUBJECTS WITH NORMAL RENAL FUNCTION. NO STUDIES WERE CONDUCTED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT OR IN RENAL IMPAIRMENT PATIENTS ON DIALYSIS.
AGE, SEX, RACE, AND WEIGHT
BASED ON POPULATION PHARMACOKINETIC ANALYSIS, AGE, SEX, RACE, AND BODY WEIGHT DID NOT SIGNIFICANTLY AFFECT THE NATPARA PHARMACOKINETICS.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
IN PREGNANT RATS GIVEN SUBCUTANEOUS DOSES UP TO 1000 ?G/KG/DAY DURING ORGANOGENESIS THERE WERE NO FINDINGS OBSERVED AT 123 TIMES THE 100 ?G/DAY CLINICAL DOSE BASED ON AUC. IN PREGNANT RABBITS GIVEN SUBCUTANEOUS DOSES OF 5, 10 AND 50 ?G/KG/DAY DURING ORGANOGENESIS, VARIOUS SKELETAL ALTERATIONS INCLUDING IN COMPLETE OSSIFICATION IN < 35% OF LITTERS GIVEN 10 ?G/KG/DAY WHICH WERE STATISTICALLY SIGNIFICANT BUT WITHIN HISTORICAL CONTROL RANGE AT EXPOSURES 8 TIMES THE 100 ?G/KG/DAY CLINICAL DOSE. THERE WAS A FETUS WITH SPINA BIFIDA IN THE 50 ?G/KG/DAY DOSE GROUP AT 72 TIMES THE 100 ?G/DAY CLINICAL DOSE BASED ON AUC. GIVEN THE ASSOCIATION OF FOLIC ACID DEFICIENCY AND NEURAL TUBE DEFECTS THIS FINDING MAY BE RELATED TO DECREASED BODY WEIGHT AND FOOD CONSUMPTION IN THE PREGNANT RABBITS.
DEVELOPMENTAL EFFECTS WERE OBSERVED IN A PERI-/POST-NATAL STUDY IN PREGNANT RATS GIVEN SUBCUTANEOUS DOSES OF 100, 300, 1000 ?G/KG/DAY FROM ORGANOGENESIS THROUGH LACTATION WHILE AN ENTIRE LITTER WAS STILLBORN IN THE 300 ?G/KG/DAY GROUP (34 TIMES THE 100 MCG/DAY CLINICAL DOSE BASED ON AUC) AND AN ENTIRE LITTER FROM THE 1000 ?G/KG/DAY (123 TIMES THE 100 ?G/DAY CLINICAL DOSE BASED ON AUC) WAS DEAD BY POSTNATAL DAY 4. INCREASED INCIDENCE OF MORBIDITY ASSOCIATED WITH DEHYDRATION, BROKEN PALATE AND PALATE INJURIES RELATED TO INCISOR MISALIGNMENT AND MORTALITY WERE FOUND IN PUPS FROM LITTERS GIVEN 100 MCG/KG/DAY (10 TIMES THE 100 MCG/DAY CLINICAL DOSE BASED ON AUC). AT 300 MCG/KG/DAY THERE WAS A LITTER WITH KIDNEY DILATATION AND ANOTHER WITH AN EXTRA LIVER LOBE. THERE WAS A SINGLE PUP WITH A DIAPHRAGMATIC HERNIA FROM A LITTER EXPOSED TO 1000 ?G/KG/DAY.
CLINICAL STUDIES
STUDY IN PATIENTS WITH ESTABLISHED HYPOPARATHYROIDISM
THE EFFICACY OF NATPARA WAS EVALUATED IN A 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL. IN THIS TRIAL, PATIENTS WITH ESTABLISHED HYPOPARATHYROIDISM RECEIVING CALCIUM AND ACTIVE FORMS OF VITAMIN D (VITAMIN D METABOLITE OR ANALOGS) WERE RANDOMIZED (2:1) TO NATPARA (N=84) OR PLACEBO (N=40). THE MEAN AGE WAS 47 YEARS (RANGE, 19 TO 74 YEARS), 79.0% WERE FEMALES AND 96.0% WERE CAUCASIAN, 0.8% WERE BLACK, AND 1.6% WERE ASIAN. PATIENTS HAD HYPOPARATHYROIDISM FOR ON AVERAGE 15 YEARS AND HYPOPARATHYROIDISM WAS CAUSED BY POST-SURGICAL COMPLICATIONS IN 71% OF CASES, IDIOPATHIC HYPOPARATHYROIDISM IN 25%, DIGEORGE SYNDROME IN 3%, AND AUTO-IMMUNE HYPOPARATHYROIDISM IN 1%. PATIENTS WITH HYPOPARATHYROIDISM DUE TO CALCIUM-SENSING RECEPTOR MUTATIONS WERE EXCLUDED FROM THE TRIAL. THE MEAN EGFR AT BASELINE WAS 97.4 ML/MIN/1.73 M² AND 45%, 10% AND 0% HAD MILD, MODERATE AND SEVERE RENAL IMPAIRMENT, RESPECTIVELY, AT BASELINE.
BEFORE RANDOMIZATION, PARTICIPANTS ENTERED A 2-16 WEEKS RUN-IN PHASE. IN THIS PHASE CALCIUM SUPPLEMENT AND ACTIVE VITAMIN D DOSES WERE ADJUSTED TO TARGET AN ALBUMIN-CORRECTED SERUM CALCIUM CONCENTRATION BETWEEN 8.0 AND 9.0 MG/DL AND 25-HYDROXYVITAMIN D WAS REPLACED IN PATIENTS WITH INSUFFICIENT STORES. AT RANDOMIZATION, BASELINE SERUM CALCIUM WAS 8.6 MG AND PARTICIPANTS WERE RECEIVING A MEDIAN (INTERQUARTILE RANGE) DAILY ORAL CALCIUM DOSE OF 2000 (1250, 3000) MG AND A MEDIAN DAILY ORAL ACTIVE VITAMIN D DOSE EQUIVALENT TO 0.75 MCG (0.5, 1) OF CALCITRIOL.
AT RANDOMIZATION, ACTIVE FORMS OF VITAMIN D WERE REDUCED BY 50% AND PATIENTS WERE RANDOMIZED TO NATPARA 50 MCG DAILY OR PLACEBO. RANDOMIZATION WAS FOLLOWED BY A 12-WEEK NATPARA TITRATION PHASE AND A 12-WEEK NATPARA DOSE MAINTENANCE PHASE. DURING THE TITRATION PHASE NATPARA WAS INCREASED BY 25 MCG INCREMENTS EVERY FOUR WEEKS UP TO A MAXIMUM OF 100 MCG. TITRATION WAS INDICATED FOR PATIENTS WHO COULD NOT ACHIEVE INDEPENDENCE FROM ACTIVE VITAMIN D AND WHO COULD NOT REDUCE ORAL CALCIUM TO 500 MG OR LESS PER DAY. AT END OF TREATMENT, 56% OF SUBJECTS RANDOMIZED TO NATPARA WERE RECEIVING 100 MCG OF NATPARA PER DAY, 26% WERE RECEIVING 75 MCG OF NATPARA PER DAY, AND 18% WERE RECEIVING 50 MCG OF NATPARA PER DAY. DOSES OF CO-ADMINISTERED ACTIVE FORMS OF VITAMIN D AND CALCIUM WERE ADJUSTED (REDUCED OR INCREASED) TO MAINTAIN ALBUMIN-CORRECTED SERUM CALCIUM WITHIN A DESIRED TARGET RANGE THROUGHOUT THE TRIAL IN BOTH ARMS.
FOR THE EFFICACY ANALYSIS, SUBJECTS THAT FULFILLED THREE COMPONENTS OF A THREE-PART RESPONSE CRITERION WERE CONSIDERED RESPONDERS. A RESPONDER WAS DEFINED AS AN INDIVIDUAL WHO HAD: AT LEAST A 50% REDUCTION FROM BASELINE IN THE DOSE OF ACTIVE VITAMIN D, AT LEAST A 50% REDUCTION FROM BASELINE IN THE DOSE OF ORAL CALCIUM SUPPLEMENTATION AND AN ALBUMIN-CORRECTED TOTAL SERUM CALCIUM CONCENTRATION BETWEEN 7.5 MG/DL AND 10.6 MG/DL.
AT THE END OF TREATMENT, SIGNIFICANTLY (P-VALUE < 0.001) MORE SUBJECTS TREATED WITH NATPARA [46/84 (54.8%)] COMPARED TO PLACEBO [1/40 (2.5%)] MET THE RESPONSE CRITERION. FORTY-TWO PERCENT (35/84) OF SUBJECTS RANDOMIZED TO NATPARA WERE INDEPENDENT OF ACTIVE FORMS OF VITAMIN D AND WERE ON NO MORE THAN 500 MG OF ORAL CALCIUM, COMPARED WITH 2.5% (1/40) OF SUBJECTS RANDOMIZED TO PLACEBO (P < 0.001). THERE WERE NO DIFFERENCES IN THE PROPORTION OF PATIENTS WITH A CALCIUM LEVEL BETWEEN 7.5 MG AND 10.6 MG AT END OF TREATMENT BETWEEN SUBJECTS RANDOMIZED TO NATPARA AND PLACEBO.
TABLE 6 SHOWS THE PROPORTION OF INDIVIDUALS WHO, AT THE END OF TREATMENT, FULFILLED THE 3 PART RESPONSE CRITERION. TABLE 7 PROVIDES RESULTS ON INDIVIDUAL COMPONENTS OF THE RESPONSE CRITERION.
TABLE 6: PROPORTION OF RESPONDERS* AT END OF TREATMENT- INTENT TO TREAT POPULATION
PLACEBO
(N=40) NATPARA
(N=84)
EFFICACY ENDPOINT
RESPONDER* AT END OF TREATMENT, BASED ON INVESTIGATOR-PRESCRIBED DATA - N (%) 1 (2.5) 46 (54.8)
(P < 0.001)A
A BASED ON FISHER'S EXACT TEST
*RESPONSE = AT LEAST A 50% REDUCTION FROM BASELINE IN THE DOSE OF ACTIVE VITAMIN D + AT LEAST A 50% REDUCTION FROM BASELINE IN THE DOSE OF ORAL CALCIUM SUPPLEMENTATION + AN ALBUMIN-CORRECTED TOTAL SERUM CALCIUM CONCENTRATION BETWEEN 7.5 MG/DL AND 10.6 MG/DL
TABLE 7: PROPORTION OF PATIENTS WITH CALCIUM AND ACTIVE VITAMIN D DOSE REDUCTION AND ALBUMIN-CORRECTED SERUM CALCIUM BETWEEN 7 AND 10.6 MG AT END OF TREATMENT - ITT POPULATION
COMPONENTS OF THE EFFICACY ENDPOINT
PLACEBO
(N=40) NATPARA
(N=84)
ORAL CALCIUM REDUCTION ? 50% - N (%) 3 (7.5) 58 (69.0)
PERCENT CHANGE FROM BASELINE -MEAN (SD) A 6.5 (38.5) -51.8 (44.6) (P < 0.001)
ORAL ACTIVE VITAMIN D REDUCTION ? 50% - N (%) 18 (45.0) 73 (86.9)
ACSC MAINTAINED BETWEEN ? 7.5 MG/DL TO ? ULN - N (%) 35 (87.5) 73 (86.9)
ACSC = ALBUMIN-CORRECTED TOTAL SERUM CALCIUM; EOT = END OF TREATMENT; N = TOTAL NUMBER OF SUBJECTS; N = NUMBER OF SUBJECTS MEETING THE SPECIFIED ENDPOINT; SD = STANDARD DEVIATION; ULN = UPPER LIMIT OF NORMAL
A BASED ON ANALYSIS OF COVARIANCE (ANCOVA) MODEL WITH PERCENT CHANGE AS THE DEPENDENT VARIABLE AND THE TREATMENT AS THE FACTOR AND BASELINE CALCIUM DOSE AS THE COVARIATE.