CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`2109060rigl s000
`
`NON-CLINICAL REVIEW(S)
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`DEPARTMENT OF HEAL TH AND HUMAN SERVICES
`PUBLIC HEAL TH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`
`NDA210906
`
`Supporting document/s:
`
`SDN1, SN0000
`
`Applicant's letter date:
`
`09/29/2017
`
`CDER stamp date:
`
`09/29/2017
`
`Product:
`
`Calcium Gluconate Injection, 1 g/50 ml and 2
`
`g/100 ml (20 mg/ml)
`
`Indication:
`
`Acute treatment of symptomatic hypocalcemia
`
`Applicant:
`
`HQ Specialty Pharma Corporation
`
`Review Division:
`
`Division of Metabolism and Endocrine Products
`
`Reviewer:
`
`Arulasanam K. Thilagar, Ph.D.
`
`Supervisor/Team Leader:
`
`C. Lee Elmore, Ph.D.
`
`Division Director:
`
`William Chong, M.D. (Acting)
`
`Project Manager:
`
`Meghna Jairath
`
`Disclaimer
`
`information discussed below and
`Except as specifically identified, all data and
`necessary for approval of NOA 210906 are owned by HQ Specialty Pharma Corporation
`or are data for which HQ Specialty Pharma Corporation has obtained a written right of
`reference. Any information or data necessary for approval of NOA HQ Specialty Pharma
`Corporation 210906 that HQ Specialty Pharma Corporation does not own or have a
`written right to reference constitutes one of the following: (1) published literature, or (2)
`a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug's
`approved labeling. Any data or information described or referenced below from reviews
`or publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of NOA 210906.
`
`
`
`Reference ID: 4327755Reference ID: 4342638
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`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMMARY ........................................................................................... 4
`1.1
`INTRODUCTION ..................................................................................................... 4
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... .4
`1.2
`ECOMMENDATIONS
`1.3 R
`............................................................................................. 5
`2 DRUG ........................................................................................................................ 7
`DRUG IDENTITY ..................................................................................................... ?
`2.1
`2.2
`RELEVANT INDs, NDAs, BLAS AND DMFs ............................................................ 8
`RUG
`2.2
`D
`FORMULATION ............................................................................................ 8
`2.3
`CONTAINER CLOSURE SYSTEM .............................................................................. 9
`2.4
`COMMENTS ON NOVEL EXCIPIENTS ...................................................................... 11
`/D
`2.5
`COMMENTS ON IMPURITIES EGRADANTS OF CONCERN ........................................ 12
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ..................................... 18
`2.7
`REGULATORY BACKGROUND ............................................................................... 19
`3 STUDIES SUBMITTED ........................................................................................... 20
`
`3.1
`STUDIES REVIEWED ............................................................................................ 20
`INTEGRATED SUMMARY AND SAFETY EVALUATION ..................................... 20
`
`4
`
`5 LITERATURE CITATIONS ..................................................................................... 23
`
`6 APPLICANT SUGGESTED LABELING ................................................................. 24
`
`7 APPENDIX/ATTACHMENTS .................................................................................. 28
`
`LETTERS OF AUTHORIZATION FROM THE MANUFACTURER ...................................... 28
`7.1
`7.2 GMP AND SITE REGISTRATION STATEMENT ......................................................... 29
`(b) (4)
`7.3 _____ cGMP CERTIFICATE ..................................................................... 30
`(b) (4)
`HQ SPECIAL TY PHARMA CORPORATION AUTHORIZATION FOR
`7.4
`NJECTION
`, 1 G/50 ML AND 2 G/100 ML (20
`TO SUBMIT CALCIUM GLUCONATE I
`MG/ML) NDA ................................................................................................................. 31
`7.5
`FDA ESTABLISHMENT INSPECTION REPORT ......................................................... 32
`
`
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`Table of Tables
`
`Table 1: Components of Calcium Gluconate Injection ..................................................... 8
`Table 2: Composition of Calcium Gluconate Injection (1 g/50 ml) .................................. 8
`Table 3: Composition of Calcium Gluconate Injection (2 g/100 ml) ................................ 9
`Table 4: Description of the Container Closure System ................................................... 1 O
`able 5: Excioients i Dru(cid:143) -. .e oduc
`1
`(b) (4)
`
`Table 14: Dosing Recommendations in mg of Calcium Gluconate for Neonate, Pediatric,
`and Adult Patients ........................................................................................................... 18
`
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`
`1
`
`Executive Summary
`
`Introduction
`1.1
`HQ Specialty Pharma Corporation (the "Applicant") seeks approval to market Calcium
`Gluconate Injection via the 505(b)(2) regulatory pathway through reliance on FDA's
`prior findings of safety and efficacy for the approved drug, Calcium Gluconate Injection,
`USP 10% (Fresenius Kabi; NOA 208418) as listed in the FDA Orange Book, hereafter
`referred to as the "listed drug" or "lD".
`
`__ .,.
`
`Calcium Gluconate Injection is intended for the treatment of acute, symptomatic
`hypocalcemia and is available in 1000 mg/per 50 ml or 2000 mg per 100 ml single use
`(b) (4)
`bags. Each milliliter of Calcium Gluconate Injection contains 20 mg of calcium
`gluconate (18.8 mg of calcium gluconate and 0.9 mg of calcium D-saccharate
`tetrahydrate), 6.75 mg/ml sodium chloride, hydrochloric acid and/or sodium hydroxide
`for pH adjustment (pH 6.0 to 8.2). The required clinical dose is dependent upon the
`serum calcium levels of individual patients. The route of administration and dosing
`regimen (dose,
`frequency, and duration) for the Applicant's premixed Calcium
`Gluconate Injection product is similar to that of the listed drug's, once the lD is diluted
`for administration.
`
`1.2 Brief Discussion of Nonclinical Findings
`Mechanism of Action, Metabolism and General Toxicity
`Many vital cellular biological processes, such as blood coagulation, neuromuscular
`excitability, maintenance of cell membrane integrity, and cellular homeostasis are
`dependent on maintenance of adequate free ionized plasma calcium concentrations.
`
`Calcium gluconate metabolism is limited to the gluconate component of the salt, as
`ionized calcium itself does not undergo direct metabolism. Gluconate is a normal
`product of glucose metabolism. The daily production of gluconate from endogenous
`sources is estimated to be about 450 mg for a 60 kg person, which amounts to 27 g or
`more than twice the estimated daily intake of gluconate from the proposed maximum
`dose (12 g) of Calcium Gluconate Injection for the treatment of hypocalcemia (American
`Societies for Experimental Biology (1975)).
`
`The Applicant conducted no nonclinical studies to support the safety of Calcium
`Gluconate Injection and provided no literature references for the primary pharmacology,
`secondary
`pharmacology,
`safety
`pharmacology,
`pharmacokinetics,
`safety
`pharmacology, general
`toxicology, genotoxicity, carcinogenicity, reproductive and
`developmental toxicity, or local tolerance. Instead, the Applicant seeks to rely upon the
`FDA's previous findings of safety and efficacy of the listed drug (NOA 208418) as the
`sole source of information to support this 505(b)(2) submission.
`
`Calcium toxicity in laboratory animals is primarily due to hypercalcemia, including soft
`tissue mineralization, especially in the kidneys, hypercalciuria, nephropathy, weight loss
`(due to decreased food consumption), altered bone metabolism, decreased clotting
`
`
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`time, abnormal heart rhythms and neurologic effects. Long-term studies in animals have
`not been conducted to evaluate the carcinogenic potential of Calcium Gluconate
`Injection. Calcium gluconate was not mutagenic with or without metabolic activation in
`the Ames test with Salmonella typhimurium. No animal reproduction studies were
`conducted with the LD, but adequate calcium levels are expected to be required during
`pregnancy. Glucono-delta-lactone administration had no effect on implantation or on
`maternal or fetal survival in mice, rats, hamsters and rabbits.
`
`Excipients
`
`Calcium Gluconate Injection contains no novel excipients.
`
`Impurities of Toxicological Concern
`
`Calcium mineral (the mined source of calcium in Calcium Gluconate Injection) contains
`a variety of metal impurities, which may vary widely by source. The metal of
`toxicological concern in Calcium Gluconate Injection is aluminum. Aluminum is a
`potentially toxic to the CNS and bone with exposure by the intravenous route, especially
`in patients with poor renal function, including neonates. However, at the maximum
`recommended doses of Calcium Gluconate Injection, and based on the Applicant's
`proposed release specification for aluminum, the daily aluminum exposure will be below
`4 mcg/kg/day, levels associated with central nervous system and bone toxicity in
`patients with impaired kidney function, including premature neonates. Tissue loading
`may occur at even lower rates of administration, but Calcium Gluconate for Injection is
`indicated only for acute use until calcium homeostasis is restored.
`
`1.3 Recommendations
`
`1.3.1 Approvability
`This NOA is approvable from the Pharm/Tox perspective.
`1.3.2 Additional Nonclinical Recommendations
`The product labeling should clearly state the aluminum levels in Calcium Gluconate
`Injection, to inform the risk of off-label use for longer-term calcium administration (e.g.,
`via total parenteral nutrition).
`1.3.3 Labeling
`Reviewer's Recommended Labeling~: _________________ _
`
`INDICATIONS AND USAGE
`
`Calcium Gluconate Injection is a form of calcium indicated for pediatric and adult
`patients for the treatment of acute symptomatic hypocalcemia.
`
`Limitations of Use
`The safety of Calcium Gluconate Injection for long term use has not been established.
`
`
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`
`5 WARNINGS AND PRECAUTIONS
`
`5.5 Aluminum Toxicity
`
`Calcium Gluconate Injection contains aluminum, up to 25 mcg per liter, that may be
`toxic. Aluminum may reach toxic levels with prolonged parenteral administration if
`kidney function is impaired. Premature neonates are particularly at risk because their
`kidneys are immature, and they require large amounts of calcium and phosphate
`solutions, which contain aluminum. Research indicates that patients with impaired
`kidney function,
`including premature neonates, who receive parenteral levels of
`aluminum at greater than 4 mcg/kg/day to 5 mcg/kg/day accumulate aluminum levels
`associated with central nervous system and bone toxicity. Tissue loading may occur at
`even lower rates of administration.
`
`8
`
`Use in Specific Populations
`
`8.1
`
`Pregnancy
`
`Risk Summary (Nonclinical portion only)
`No animal reproduction studies have been conducted with Calcium Gluconate Injection.
`
`8.2
`
`Lactation
`
`Risk Summary (Nonclinical portion only)
`[In the absence of animal data, no statement based on animals should be included.]
`
`12
`
`Clinical Pharmacology
`
`12.1 Mechanism of Action
`
`Intravenous administration of calcium gluconate increases serum ionized calcium level.
`Calcium gluconate dissociates into ionized calcium in plasma. Ionized calcium and
`(b) (4)
`constituents of body fluids.
`gluconate are -
`
`13
`
`Nonclinical Toxicology
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Long-term studies in animals have not been conducted to evaluate the carcinogenic
`potential of Calcium Gluconate Injection. Calcium gluconate was not mutagenic with or
`(strains TA-
`without metabolic activation in the Ames test with Salmonella typhimurium
`1535, TA-1537, and TA-1538) or Saccharomyces cerevisiae (Strain D4). Fertility studies
`in animals have not been conducted with calcium gluconate administered by the
`intravenous route.
`
`
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`2
`
`Drug
`
`2.1
`
`Drug identity
`
`Reviewer: Arulasanam K. Thilagar, PhD
`
`Name
`Calcium Gluconate Injection, 1 g/50 ml and 2 g/100 ml (20 mg/ml)
`
`CAS Registry Number
`18016-24-5
`
`Generic Name
`Calcium gluconate
`
`Chemical Name
`Calcium gluconate monohydrate
`
`Molecular Formula/Molecular Weight
`C12H22CaO14 · H2O I 448.39
`
`Structure or Biochemical Description
`
`HO
`
`o-
`
`Ca2
`
`· HO
`2
`
`2
`
`Pharmacologic Class
`Calcium
`
`Manufacturer of API
`
`(b) (4)
`
`Letter of Authorizations from Manufacturer of API
`(b) (4)
`Provided in the Appendix - DMF Type II -
`
`Manufacturer of Calcium Gluconate Injections (1 g/50ml and 2 g/100ml)
`(b) (4)
`
`(b) (4)
`
`~~~-~
`
`received a satisfactory FDA inspection August 8th -16th, 2016. A copy of
`the FDA cGMP acceptability letter is included (see Appendix). Also included, is a copy
`(b) (4)
`of cGMP certification for
`
`
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`
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`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`NOA 208418 - Calcium Gluconate Injection, USP 10%
`(b) (4)
`DMF
`
`2.2 Drug Formulation
`
`The components and composition of the final drug product and the function of each
`excipient are given below.
`
`Table 1: Components of Calcium Gluconate Injection
`Name of Ingredients
`Grade
`Calcium Gluconate
`USP
`Calcium D-Saccharate
`USP
`(tetrahydrate)
`HCI/NaOH
`Sodium Chloride
`
`NF
`USP
`
`Function
`Active Ingredient
`
`Tonicity Agent
`
`(b) (4)
`
`(b) (4)
`
`I
`
`Table 2: Composition of Calcium Gluconate Injection (1 g/50 ml)
`Composition
`Amount per ml
`Amount per 50 ml
`(mg)
`(mg)
`(b) (4)
`(b) (4)
`I
`I
`(18.8)
`
`Name of Ingredients
`
`Calcium Gluconate Monohydrate
`I
`l
`(b) (4)
`
`I
`
`(940)
`
`I
`
`Calcium D-Saccharate
`(tetrahydrate)
`HCI/NaOH
`
`Sodium Chloride
`
`Total Volume
`
`0.9
`
`qs
`
`6.75
`
`1 ml
`
`45
`
`qs
`
`337.5
`
`50 ml
`
`(b) (4)
`
`
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`
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`
`Table 3: Composition of Calcium Gluconate Injection (2 g/100 ml)
`Composition
`
`Name of Ingredients
`
`Amount per ml
`(mg)
`(b) (4)
`I
`I
`(18.8)
`0.9
`
`Amount per 100 ml
`(mg)
`(b) (4)
`I
`I
`(1880)
`90
`
`qs
`6.75
`
`1 ml
`
`qs
`675
`
`100 ml
`
`(b) (4)
`
`Calcium Gluconate Monohydrate
`-I
`I
`(b) (4)
`Calcium D-Saccharate
`(tetrahydrate)
`HCI/NaOH
`Sodium Chloride
`
`Total Volume
`
`Description of Dosage Form
`
`Calcium Gluconate Injection, 1 g/50 ml and 2 g/100 ml (20 mg/ml) is a ready to infuse
`(b) (4)
`solution in
`- - - - bags. The drug product is stored at room temperature
`(b) (4)
`
`2.3 Container Closure System
`
`Calcium Gluconate Injection, 1 g/50 ml and 2 g/100 ml 20 mg/ml) is packaged in
`(b) (4)
`single use 100 ml bags ~ - - - - - ---- - -~- _______
`, containing a
`(b) (4)
`pre-printed label. The bags contain a single port. The bags are placed in a
`,-"-- aluminum overwrap with pre-printed labels using green and blue and black
`ink. The bags are made of
`
`(b) (4)
`
`The Applicant provided a summary of components used in container closure system
`and the manufacturers/suppliers and DMF numbers.
`
`
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`
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`
`Table 4: Description of the Container Closure System
`Description of the Container Closure System
`Component
`Raw Material Supplier
`Supplier
`
`DMF
`number
`
`(b) (4)
`
`(b) (4)
`
`Not
`available*
`
`Container
`Closure
`System
`(b) (4)
`
`_ __}100
`;-
`ml bags
`
`(b) (4)
`
`Port:
`rTwist off port
`
`Overwrap
`
`(b) (4)
`
`I 100 ml bag,
`
`(b) (4)
`
`Each bag is over-wrapped I r
`
`(b) (4)
`
`(b) (4)
`
`A:luminium
`
`nk
`
`Pigment Ink
`
`(b) (4)
`
`*Component does not contact the drug material and therefore does not require a
`DMF.
`
`
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`
`Reviewer: Arulasanam K. Thilagar, PhD
`
`Note: the container closure system is used I
`
`I
`
`(b) (4)
`
`(b) (4)
`
`The compatibility of the product with the excipients and packaging material has been
`evaluated during the stability studies performed at normal and accelerated conditions
`and the results obtained have shown that the product is stable and therefore a shelf life
`of 24 months is proposed. Applicant stated that the stability studies will continue until 36
`(b) (4)
`months
`
`2.4 Comments on Novel Excipients
`No novel excipients are used in the manufacture of Calcium Gluconate Injection. The
`excipients contained in Calcium Gluconate Injection, 1 g/ 50 ml and 2 g/ 100 ml (20
`mg/ml) are listed in the Table below.
`
`Table 5: Excipients in Drug Product
`Excipients
`Quantity (mg/ml)
`
`Calcium D-Saccharate
`(tetrahydrate)
`Sodium Chloride
`Hydrochloric Acid
`Sodium Hydroxide
`
`0.9
`
`6.75
`qs to pH
`qs to pH
`
`Function
`(b) (4)
`
`j
`
`Tonicity agent
`pH adjuster
`pH adjuster
`
`(b) (4)
`
`Calcium D-saccharate, sodium hydroxide and hydrochloric acid are present in the Listed
`(b) (4)
`Drug's concentrate formulation.
`
`Glucarate is
`transported in the blood to a number of different organs in Sprague-Dawley rats
`
`~--
`
`
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`(Walaszek, 1997). Hydrochloric acid and sodium hydroxide are listed in FDA's IIG list
`for intravenous use. The amounts of these excipients are low as they are only used for
`pH adjustment.
`
`2.5 Comments on lmpurities/Degradants of Concern
`No organic impurities were noted in the Calcium Gluconate Monohydrate impurity
`profile. No Class 1, Class 2 or Class 3 solvents are used in the manufacture of Calcium
`Gluconate Monohydrate. Therefore, there is no solvents are present in Calcium
`(b) (4)
`Gluconate Monohydrate.
`
`(b) (4)
`
`
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`
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`
`The Applicant is using the calcium gluconate from a supplier,
`
`(b) (4)
`
`There are no safety concerns from the additional impurities originating from the
`excipients used.
`
`(b) (4)
`
`(b) (4)
`
`13
`4 Page have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
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`Proposed Clinical Population and Dosing Regimen
`2.6
`Calcium Gluconate Injection is a form of calcium indicated for pediatric and adult
`patients for the treatment of acute symptomatic hypocalcemia. The dose of Calcium
`Gluconate Injection is dependent on the requirements of the individual patient. Calcium
`is provided
`in
`ready-to-use
`formulations
`for
`intravenous
`Gluconate
`Injection
`administration to infants, pediatric and adult patients. Calcium Gluconate Injection is a
`solution available in single use bags with aluminum overwrap for injection. Each ml of
`Calcium Gluconate Injection contains 1.86 mg (0.093 mEq) of elemental calcium.
`
`Table 14: Dosing Recommendations in mg of Calcium Gluconate for Neonate,
`Pediatric, and Adult Patients
`Patient Population
`Initial Dose
`
`SubseQuent Doses (if needed)
`Bolus
`Continuous
`1 month) 100 - 200 mg/kg 100 - 200 mg/kg
`Initiate at 17-33
`every 6 hours
`mg/kg/hour
`
`Neonate
`
`(≤
`
`Pediatric (> 1 month 29 - 60 mg/kg
`to< 17 years)
`Adult
`
`29-60 mg/kg
`every 6 hours
`1000 - 2000 mg 1 ooo - 2000 mgL
`(b) (4)
`every 6 hours
`For bolus administration, DO NOT exceed an infusion rate of:
`•200 mg/minute in adult patients
`•100 mg/minute in pediatric patients
`For continuous infusions, adjust rate as needed based on serum calcium levels
`
`Initiate at 8-13
`mg/kg/hour
`Initiate at 5.4 - 21.5
`mg/kg/hour
`
`The proposed clinical labeling recommends the following dosage in pregnant woman
`
`Limited available data with Calcium Gluconate Injection use in pregnant women are
`insufficient to inform a drug associated risk of adverse developmental outcomes. There
`are risks to the mother and the fetus associated with hypocalcemia in pregnancy. The
`estimated background risk of major birth defects and miscarriage for the indicated
`population is unknown. In the U.S., general population, the estimated background risk of
`major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-
`20%, respectively.
`
`The proposed clinical labeling recommends the following dosage in neonates and
`pediatric patients:
`
`Infants born to mothers with hypocalcemia can have associated fetal and neonatal
`hyperparathyroidism, which
`in
`turn can cause
`fetal and neonatal skeletal
`demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal
`seizures. Infants born to mothers with hypocalcemia should be carefully monitored for
`signs of hypocalcemia or hypercalcemia, including neuromuscular irritability, apnea,
`cyanosis and cardiac rhythm disorders.
`
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`
`Reviewer: Arulasanam K. Thilagar, PhD
`
`The safety and effectiveness of Calcium Gluconate Injection have been established in
`pediatric patients for the treatment of acute, symptomatic hypocalcemia. Pediatric
`approval for Calcium Gluconate Injection, including doses, is not based on adequate
`and well-controlled clinical studies. Safety and dosing recommendations in pediatric
`patients are based on published literature and clinical experience.
`
`Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in
`neonates (28 days of age or younger) due to reports of fatal outcomes associated with
`the presence of lung and kidney ceftriaxone-calcium precipitates. In patients, older than
`28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered
`sequentially, provided the infusion lines are thoroughly flushed between infusions with a
`compatible fluid.
`
`The proposed label recommends the following dosage in geriatric, renal impairment and
`Hepatic impairment patients:
`
`In general dose selection for an elderly patient should start at the lowest dose of the
`recommended dose range, reflecting the greater frequency of decreased hepatic, renal,
`or cardiac function, and of concomitant disease or other drug therapy.
`
`For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest
`dose of the recommended dose ranges across all age groups. Monitor serum calcium
`levels every 4 hours
`
`Hepatic function does not impact the availability of ionized calcium after calcium
`gluconate intravenous administration. Dose adjustment in hepatically impaired patients
`may not be necessary.
`
`2.7 Regulatory Background
`The Applicant submitted NOA 210906 for Calcium Gluconate Injection 1 g/50 ml and 2
`g/100 ml (20 mg/ml) under section 505(b)(2) pathway. The filing is based upon the
`Orange Book listed drug (lD) Calcium Gluconate Injection (NOA 208418). The holder
`of the NOA 208418 is Fresenius Kabi.
`
`The calcium gluconate API is manufactured by
`applicant provided a letter authorizing FDA to reference
`(b) (4)
`TypellDMF -
`
`(b) (4)
`
`(b) (4)
`
`The Applicant submitted NOA 210906 on September 29, 2017. No IND related to this
`submission was noted. The Applicant submitted a full waiver for the Initial Pediatric
`Study Plan (iPSP) on October 4, 2017.
`
`The applicant submitted an amendment on October 30, 2017 in response to the
`Information Request dated October 26, 2017 from FDA. The Applicant submitted
`Patent Certification (Form 3542a) on December 30, 2017. The Applicant submitted a
`response on December 15, 2017 to FDA Information Request dated November 15,
`
`
`
`Reference ID: 4327755Reference ID: 4342638
`
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`2017. The Applicant submitted a response on February 5, 2018 to FDA Information
`Request dated January 4, 2018. The Applicant submitted an Amendment (updated 356
`H). This Amendment was to correct the lD application number. The Applicant submitted
`a response on March 23, 2018 to FDA Information Request dated February 22, 2018.
`The Applicant submitted a response on April 5, 2018 to FDA Information Request dated
`March 30, 2018.
`
`3
`
`Studies Submitted
`
`Studies Reviewed
`3.1
`No new nonclinical studies have been conducted by the Applicant. The Applicant relies
`solely on the FDA's previous findings of safety and efficacy for NOA 208418 to support
`its 505(b)(2) submission.
`
`The route of administration and dosing regimen (dose, frequency, and duration) for the
`Applicant's premixed Calcium Gluconate Injection product are the same as the listed
`drug's.
`4
`Integrated Summary and Safety Evaluation
`The Applicant filed this NOA to market Calcium Gluconate Injection via the 505(b)(2)
`regulatory pathway. Calcium Gluconate Injection is intended for the treatment of acute,
`symptomatic hypocalcemia. The Applicant conducted no nonclinical studies or provided,
`literature references for the primary pharmacology, secondary pharmacology, safety
`pharmacology,
`pharmacokinetics,
`safety
`pharmacology,
`general
`toxicology,
`genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance,
`or other toxicities. The Applicant relies on the FDA's previous findings of safety and
`efficacy of the approved drug, Calcium Gluconate Injection, USP 10% (NOA 208418) as
`the sole source to support this 505(b)(2) submission. The route of administration and
`dosing regimen (dose, frequency, and duration) for the Applicant's premixed Calcium
`Gluconate Injection product will be same as the Calcium Gluconate Injection listed
`drug's once the lD is diluted.
`
`Calcium Gluconate Injection is available as 1000 mg/per 50 ml (18.8 mg/ml) or 2000
`(b) (4)
`mg per 100 ml single use,
`bags with aluminum overwrap. Each 1 ml of
`Calcium Gluconate Injection contains 20 mg of calcium gluconate (equivalent to 18.8
`mg of calcium gluconate and 0.9 mg of calcium D-saccharate tetrahydrate), 6.75 mg/ml
`sodium chloride, hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 6.0
`to 8.2). The materials used for forming the bags comply with the US Pharmacopoeia,
`current edition, and with the FDA - Regulation 21 CFR 201.56. The container closure
`(b) (4)
`system
`
`Calcium is the major extracellular divalent cation in mammals. More than 95% of total
`physiologic calcium is located within osseous tissues and the remaining amount of
`
`
`
`Reference ID: 4327755Reference ID: 4342638
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`
`physiologic calcium is present in small amounts in extracellular fluids and to a minor
`In the plasma, about 45% of ionized calcium is protein bound,
`extent within cells.
`primarily to albumin, with about 10% being complexed with anionic buffers, such as
`citrate and phosphate. The remaining fraction of "free" ionized calcium is the component
`that exerts physiological effects. Reduction of calcium below normal levels results in the
`manifestation of overt hypocalcemia symptoms. Many vital cellular biological processes,
`as well as cell membrane integrity and cell function, are known to be dependent upon
`maintenance of adequate ionized plasma calcium concentrations (Jain, 201 O; Zaloga,
`1992).
`
`Under normal physiologic conditions, extracellular calcium levels are regulated by
`endocrine control; which affects calcium uptake at the level of the intestine and ultimate
`excretion at the level of the kidney with secondary renal associated regulation of
`compartmentalized calcium (within osseous tissues) enabling calcium release from
`sequestered stores in times of physiological need (Zaloga, 1992). Significant amounts
`of calcium are secreted in milk during lactation in mammals post-parturition.
`
`The extracellular calcium concentration has three primary regulators: Calcium-sensing
`receptor (CaSR), parathyroid hormone (PTH), and vitamin D. The CaSR is a
`membrane-bound receptor found in multiple tissues, including cells of the parathyroid
`glands. When plasma ionized calcium concentrations are sufficient to stimulate the
`CaSR, the result is inhibited PTH release. When the ionized calcium concentration is
`low, PTH is released and is carried in blood to its target tissues: bone and kidney (Zhou,
`2009). Intravenous administration of calcium gluconate in combination with Vitamin D
`has been observed to significantly increase bone mineralization in rabbits (Lani, 2014).
`Intravenous administration of calcium gluconate increases serum ionized calcium level.
`Calcium gluconate dissociates into ionized calcium in plasma. Ionized calcium and
`gluconate are normal constituents of body fluids. Information on the toxicity of calcium
`gluconate in the literature show that calcium toxicity is associated with hypercalcemia in
`laboratory animals, consisting of soft tissue mineralization, especially in the kidneys,
`hypercalciuria, nephropathy, weight loss (due to decreased food consumption), altered
`bone metabolism, decreased clotting time, abnormal heart rhythms and altered behavior
`(i.e., neurologic effects).
`
`The mutagenic potential of calcium gluconate has been evaluated and Calcium
`gluconate has been shown to be negative in mutagenicity assays conducted in bacteria
`and yeast. Calcium Gluconate Injection has not been evaluated in lifetime rodent
`carcinogenicity studies. Glucono-delta-lactone (a neutral cyclic ester of gluconic acid in
`equilibrium with gluconic acid in solution) did not induce compound-related tumors in a
`2-year feeding study in rats. No animal reproduction studies were conducted with
`Calcium Gluconate Injection. Adequate calcium levels are expected to be beneficial
`during pregnancy. Glucono-delta-lactone administration had no effect on implantation or
`on maternal or fetal survival in mice, rats, hamsters and rabbits.
`
`No novel excipients are used in the manufacture of Calcium Gluconate Injection.
`Calcium D-saccharate, sodium hydroxide and hydrochloric acid are present in the Listed
`
`
`
`Reference ID: 4327755Reference ID: 4342638
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`Reviewer: Arulasanam K. Thilagar, PhD
`
`Drug's concentrate formulation. Calcium saccharate is listed in the USP monograph for
`Calcium Gluconate Injection, USP. The Sodium Chloride, USP, Hydrochloric Acid 37%,
`NF, and Sodium Hydroxide, NF used in the drug product comply with current USP/NF
`compendia requirements. Hydrochloric acid and sodium hydroxide are listed in FDA's
`IIG list for intravenous use. The amounts of these excipients are low as they are only
`used for pH adjustment. Sodium chloride used for manufacture Calcium Gluconate
`Injection meets pharmacopeia requirements (USP and Ph. Eur. Monograph) with
`associated elemental impurities limits. No metal catalyst or reagents are added
`intentionally to sodium chloride.
`
`No organic impurities were noted
`substance impurity profile.
`
`in the Calcium Gluconate Monohydrate drug
`
`Calcium D-saccharate is
`
`resent in Calcium Gluconate In·ection.
`
`(b) (4)
`
`(b) (4)
`
`CFR21 part 201 subpart 201-323 specifies that the amount of aluminum for small
`volume parenteral drug products shall be stated in product labeling. The Applicant
`analyzed elemental impurities in in six batches of Calcium Gluconate injections. The
`(b) (4)
`(b) (4)
`mcg/ml.
`aluminum levels in these six batches were
`
`Premature neonates are particularly at risk of aluminum toxicity because their kidneys
`are immature, and they require large amounts of calcium and phosphate solutions,
`which contain aluminum. Research indicates that patients with impaired kidney