CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 21817/S-012
`
`RECLAST
`
`Zoledronic Acid
`
`Novartis Pharmaceuticals Corp.
`
`8/31/2011
`
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` Reclast is a bisphosphonate indicated for:
`
` Treatment and prevention of postmenopausal
`osteoporosis
`
` Treatment to increase bone mass in men with
`osteoporosis
`
` Treatment and prevention of glucocorticoid-induced
`osteoporosis
`
` Treatment of Paget’s disease of bone in men and
`women
`
` 
`
` 
`
` 
`
`
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21817/S-012
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
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`
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`X
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`X
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`X
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`X
`X
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`

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`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21817/S-012
`NDA 21817/S-012
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`APPLICATION NUMBER:
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`APPROVAL LETTER
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`APPROVAL LETTER
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`
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`
`
`

`

`
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
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`
` NDA 21817/S-012
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`
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`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
`
`
`Novartis Pharmaceuticals Corp.
`Attention: Bijal Pandi, Pharm.D.
`Global Program Regulatory Manager
`One Health Plaza
`East Hanover, NJ 07936
`
`Dear Dr. Pandi:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received May 13,
`2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Reclast® (zoledronic acid) Injection 5 mg in a 100 mL ready-to-infuse solution.
`
`We acknowledge receipt of your amendments dated August 15 and 30, 2011.
`
`This “Prior Approval” supplemental new drug application provides for changes to the
`CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION, WARNINGS AND
`PRECAUTIONS, USE IN SPECIAL POPULATIONS, CLINICAL PHARMACOLOGY,
`and PATIENT COUNSELING INFORMATION sections of the physician insert regarding
`renal impairment, specifically creatinine clearance. This supplement also provides for changes
`to the Medication Guide to be consistent with the changes in the physician labeling.
`
`We also note in your submission your intent to issue a “Dear Healthcare Provider Letter”
`
`regarding these changes.
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and Medication
`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
`
`
`Reference ID: 3008875
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`

`

` NDA 21817/S-012
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`Page 2
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`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Division of Drug Marketing, Advertising, and Communications
`(DDMAC), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`
`
`Reference ID: 3008875
`
`

`

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` NDA 21817/S-012
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`Page 3
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` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`If you have any questions, call Jennifer Mercier, Chief, Project Management Staff, at (301) 796­
`0957.
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`George Benson, M.D.
`Deputy Director
`Division of Reproductive and Urologic Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Content of Labeling
`Medication Guide
`
`
`
`Reference ID: 3008875
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GEORGE S BENSON
`08/31/2011
`
`Reference ID: 3008875
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 21817/S-012
`NDA 21817/S-012
`
`APPLICATION NUMBER:
`
`LABELING
`
`LABELING
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`
`
`
`
`

`

`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Reclast
`SAFELY AND EFFECTIVELY. See full prescribing information for
`RECLAST.
`
`Reclast ® (zoledronic acid) Injection
`Initial U.S. Approval: 2001
`--------------RECENT MAJOR CHANGES---------------------
`Indications and Usage (1.6)
`
`
`
`01/2011
`Dosage and Administration (2, 2.6)
`
`
`03/2011
`Contraindications (4.2)
`
`
`
`
`08/2011
`Warnings and Precautions (5.3)
`
`
`
`08/2011
`Warnings and Precautions (5.5)
`
`
`
`01/2011
`--------------INDICATIONS AND USAGE---------------------
`Reclast is a bisphosphonate indicated for:
`• Treatment and prevention of postmenopausal osteoporosis (1.1, 1.2)
`• Treatment to increase bone mass in men with osteoporosis (1.3)
`• Treatment and prevention of glucocorticoid-induced osteoporosis (1.4)
`• Treatment of Paget’s disease of bone in men and women (1.5)
`The optimal duration of use has not been determined. Patients should have the
`need for continued therapy re-evaluated on a periodic basis (1.6)
`------------DOSAGE AND ADMINISTRATION-------------
`Infusion given intravenously over no less than 15 minutes:
`• Treatment of postmenopausal osteoporosis (2.1); treatment to increase bone
`mass in men with osteoporosis (2.3): treatment and prevention of glucocorticoid-
`induced osteoporosis (2.4): 5 mg once a year
`• Prevention of postmenopausal osteoporosis: 5 mg once every 2 years (2.2)
`• Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should
`receive 1500 mg elemental calcium and 800 IU vitamin D daily (2.5)
`-----------DOSAGE FORMS AND STRENGTHS------------
`5 mg in a 100 mL ready-to-infuse solution (3)
`---------------------CONTRAINDICATIONS-------------------
`• Hypocalcemia (4.1)
`• Patients with creatinine clearance <35 mL/min and in those with evidence of
`acute renal impairment (4.2, 5.3)
`• Hypersensitivity to any component of Reclast (4.3, 6.2)
`
`-----------WARNINGS AND PRECAUTIONS------------
`• Patients receiving Zometa should not receive Reclast (5.1)
`• Patients must be adequately supplemented with calcium and vitamin D (5.2)
`• A single dose should not exceed 5 mg and the duration of infusion should be
`no less than 15 minutes. Renal toxicity may be greater in patients with
`underlying renal impairment or with other risk factors, including advanced age or
`dehydration. Monitor creatinine clearance before each dose (2.1, 2.2, 5.3)
`• Osteonecrosis of the jaw has been reported. All patients should have a routine
`oral exam by the prescriber prior to treatment (5.4)
`• Atypical femur fractures have been reported. Patients with thigh or groin pain
`should be evaluated to rule out a femoral fracture (5.5).
`• Reclast can cause fetal harm. Women of childbearing potential should be
`advised (5.6, 8.1)
`• Severe incapacitating bone, joint, and/or muscle pain may occur. Withhold
`future doses of Reclast if severe symptoms occur (5.7)
`-------------------ADVERSE REACTIONS----------------------
`The most common adverse reactions (>10%) were pyrexia, myalgia, headache,
`arthralgia, pain in extremity (6.1). Other important adverse reactions were flu-
`like illness, nausea, vomiting, diarrhea (6.2), and eye inflammation (6.1).
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch.
`-------------------DRUG INTERACTIONS----------------------
`• Aminoglycosides: May lower serum calcium for prolonged periods (7.1)
`• Loop diuretics: May increase risk of hypocalcemia (7.2)
`• Nephrotoxic drugs: Use with caution (7.3)
`• Drugs primarily excreted by the kidney: Exposure may be increased with
`renal impairment. Monitor serum creatinine in patients at risk (7.4)
`------------USE IN SPECIFIC POPULATIONS-----
`Nursing Mothers: Reclast should not be given to nursing women (8 3)
`Pediatric Use: Not indicated for use in pediatric patients (8.4)
`Geriatric Use: Special care to monitor renal function (8.5)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`patient labeling
`
`
`
`
`
`Revised: 08/2011
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE 
`1.1 Treatment of Osteoporosis in Postmenopausal Women 
`1.2 Prevention of Osteoporosis in Postmenopausal Women 
`1.3 Osteoporosis in Men 
`1.4 Glucocorticoid-Induced Osteoporosis 
`1.5 Paget's Disease of Bone 
`1.6 Important Limitations of Use 
`2 DOSAGE AND ADMINISTRATION 
`2.1 Treatment of Osteoporosis in Postmenopausal Women 
`2.2 Prevention of Osteoporosis in Postmenopausal Women 
`2.3 Osteoporosis in Men 
`2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis 
`2.5 Treatment of Paget’s Disease of Bone 
`2.6 Method of Administration 
`3 DOSAGE FORMS AND STRENGTHS 
`4 CONTRAINDICATIONS 
`4.1 Hypocalcemia 
`4.2 Renal Failure 
`4.3 Hypersensitivity to Zoledronic Acid or Any Components of Reclast 
`5 WARNINGS AND PRECAUTIONS 
`5.1 Drug Products with Same Active Ingredient 
`5.2 Hypocalcemia and Mineral Metabolism 
`5.3 Renal Impairment 
`5.4 Osteonecrosis of the Jaw 
`5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures 
`5.6 Pregnancy 
`5.7 Musculoskeletal Pain 
`5.8 Patients with Asthma 
`6 ADVERSE REACTIONS 
`6.1 Clinical Studies Experience 
`6.2 Post-Marketing Experience 
`7 DRUG INTERACTIONS 
`7.1 Aminoglycosides 
`Reference ID: 3008875
`
`
`
`
`
`7.2 Loop Diuretics 
`7.3 Nephrotoxic Drugs 
`7.4 Drugs Primarily Excreted by the Kidney 
`8 USE IN SPECIFIC POPULATIONS 
`8.1 Pregnancy 
`8.3 Nursing Mothers 
`8.4 Pediatric Use 
`8.5 Geriatric Use 
`8.6 Renal Impairment 
`8.7 Hepatic Impairment 
`10 OVERDOSAGE 
`11 DESCRIPTION 
`12 CLINICAL PHARMACOLOGY 
`12.1 Mechanism of Action 
`12.2 Pharmacodynamics 
`12.3 Pharmacokinetics 
`13 NONCLINICAL TOXICOLOGY 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
`13.2 Animal Pharmacology 
`13.3 Reproductive and Developmental Toxicology 
`14 CLINICAL STUDIES 
`14.1 Treatment of Postmenopausal Osteoporosis 
`14.2 Prevention of Postmenopausal Osteoporosis 
`14.3 Osteoporosis in Men 
`14.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis 
`14.5 Treatment of Paget’s Disease of Bone 
`16 HOW SUPPLIED/STORAGE AND HANDLING 
`17 PATIENT COUNSELING INFORMATION 
`* Sections or subsections omitted from the full prescribing
`information are not listed
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Treatment of Osteoporosis in Postmenopausal Women
`Reclast is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with
`osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Reclast reduces the incidence of
`fractures (hip, vertebral and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a
`recent low-trauma hip fracture, Reclast reduces the incidence of new clinical fractures [see Clinical Studies (14.1)].
`1.2 Prevention of Osteoporosis in Postmenopausal Women
`Reclast is indicated for prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.2)].
`1.3 Osteoporosis in Men
`Reclast is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3)].
`1.4 Glucocorticoid-Induced Osteoporosis
`Reclast is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are
`either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and
`who are expected to remain on glucocorticoids for at least 12 months [see Clinical Studies (14.4)].
`1.5 Paget's Disease of Bone
`Reclast is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with
`Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the
`age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease
`[see Clinical Studies (14.5)].
`1.6 Important Limitations of Use
`The safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration.
`The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for
`continued therapy re-evaluated on a periodic basis.
`2 DOSAGE AND ADMINISTRATION
`A 5 mg dose of Reclast administered intravenously is recommended for patients with creatinine clearance ≥ 35 mL/min
`[see Warnings and Precautions (5.3)]
`Reclast is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal
`impairment [see Contraindications (4.2)].
`There are no safety or efficacy data to support the adjustment of the Reclast dose based on baseline renal function.
`Therefore, no dose adjustment is required in patients with CrCl ≥ 35 mL/min.
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`whenever solution and container permit.
`Patients must be appropriately hydrated prior to administration of Reclast [see Warnings and Precautions (5.3)].
`The i.v. infusion should be followed by a 10 mL normal saline flush of the intravenous line.
`Administration of acetaminophen following Reclast administration may reduce the incidence of acute-phase reaction
`symptoms.
`2.1 Treatment of Osteoporosis in Postmenopausal Women
`The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. For
`osteoporosis treatment, and to reduce the risk of hypocalcemia, patients must be adequately supplemented with calcium
`and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of at least 1200 mg calcium
`and 800-1000 IU vitamin D daily.
`
`Reference ID: 3008875
`
`

`

`
`2.2 Prevention of Osteoporosis in Postmenopausal Women
`The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes.
`Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal
`women require an average of 1200 mg calcium and 800-1000 IU vitamin D daily.
`2.3 Osteoporosis in Men
`The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. Patients must
`be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least 1200 mg
`calcium and 800-1000 IU vitamin D daily is recommended.
`2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
`The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. Patients
`must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least
`1200 mg calcium and 800-1000 IU vitamin D daily is recommended.
`2.5 Treatment of Paget’s Disease of Bone
`The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant
`infusion rate.
`To reduce the risk of hypocalcemia, all patients with Paget’s disease should receive 1500 mg elemental calcium daily in
`divided doses (750 mg two times a day, or 500 mg three times a day) and 800 IU vitamin D daily, particularly in the 2
`weeks following Reclast administration. All patients should be instructed on the importance of calcium and vitamin D
`supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia [see Warnings and
`Precautions (5.2)].
`Re-treatment of Paget’s Disease
`After a single treatment with Reclast in Paget’s disease an extended remission period is observed. Specific re-treatment
`data are not available. However, re-treatment with Reclast may be considered in patients who have relapsed, based on
`increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline
`phosphatase, or in those patients with symptoms, as dictated by medical practice.
`2.6 Method of Administration
`The Reclast infusion time must not be less than 15 minutes given over a constant infusion rate.
`The i.v. infusion should be followed by a 10 mL normal saline flush of the intravenous line.
`Reclast solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing
`solutions, and should be administered as a single intravenous solution through a separate vented infusion line.
`If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the
`solution is stable for 24 hours at 2°C–8°C (36°F - 46°F) [see How Supplied/Storage and Handling (16)].
`3 DOSAGE FORMS AND STRENGTHS
`5 mg in a 100 mL ready to infuse solution.
`4 CONTRAINDICATIONS
`4.1 Hypocalcemia
`[See Warnings and Precautions (5.2).]
`4.2 Renal Failure
`Reclast is contraindicated in patients with creatinine clearance < 35 ml/min and in those with evidence of acute renal
`impairment due to an increased risk of renal failure [see Warnings and Precautions (5.3)]
`4.3 Hypersensitivity to Zoledronic Acid or Any Components of Reclast
`Hypersensitivity reactions including rare cases of urticaria, angioedema, and anaphylactic reaction/shock have been
`reported [see Post-Marketing Experience (6.2)].
`
`Reference ID: 3008875
`
`

`

` 5
`
` WARNINGS AND PRECAUTIONS
`5.1 Drug Products with Same Active Ingredient
`Reclast contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated
`with Zometa should not be treated with Reclast.
`5.2 Hypocalcemia and Mineral Metabolism
`Pre-existing hypocalcemia and disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery,
`parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating
`therapy with Reclast. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly
`recommended for these patients [see Contraindications (4)].
`Hypocalcemia following Reclast administration is a significant risk in Paget’s disease. All patients should be instructed
`about the symptoms of hypocalcemia and the importance of calcium and vitamin D supplementation in maintaining serum
`calcium levels [see Dosage and Administration (2), Adverse Reactions (6.1), Information for Patients (17)].
`All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining
`serum calcium levels [see Dosage and Administration (2), Adverse Reactions (6.1), Information for Patients (17)].
`5.3 Renal Impairment
`A single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [see
`Dosage and Administration (2.1)].
`Reclast is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal
`impairment. [See Contraindications (4.2)]. If history or physical signs suggest dehydration, Reclast therapy should be
`withheld until normovolemic status has been achieved. [See Post-marketing Experience (6.2)]
`Reclast should be used with caution in patients with chronic renal impairment. Acute renal impairment, including renal
`failure, has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal
`compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration
`occurring before or after Reclast administration. Acute renal failure (ARF) has been observed in patients after a single
`administration. Rare reports of hospitalization and/or dialysis or fatal outcome occurred in patients with underlying
`moderate to severe renal impairment or with any of the risk factors described in this section [see Post-Marketing
`Experience (6.2)]. Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites
`that are primarily renally excreted [see Drug Interactions (7.4)].
`Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Reclast
`dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; interim monitoring of
`creatinine clearance should be performed in at-risk patients. Elderly patients and those receiving diuretic therapy are at
`increased risk of acute renal failure. These patients should have their fluid status assessed and be appropriately hydrated
`prior to administration of Reclast. Reclast should be used with caution with other nephrotoxic drugs [see Drug
`Interactions (7.3)]. Consider monitoring creatinine clearance in patients at-risk for ARF who are taking concomitant
`medications that are primarily excreted by the kidney [see Drug Interactions (7.4)].
`
`5.4 Osteonecrosis of the Jaw
`Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid.
`Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some
`cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates.
`A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental
`examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in
`patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, radiotherapy, corticosteroids, poor oral
`hygiene, pre-existing dental disease or infection, anemia, coagulopathy).
`While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For
`patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients
`requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment
`reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient
`based on individual benefit/risk assessment [see Adverse Reactions (6.1)].
`
`Reference ID: 3008875
`
`

`

`
`5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures
`Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients.
`These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar
`flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been
`established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
`Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and
`many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months
`before a complete fracture occurs. A number of reports note that patients were also receiving treatment with
`glucocorticoids (e.g., prednisone) at the time of fracture.
`Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of
`having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an
`atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption
`of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
`5.6 Pregnancy
`RECLAST SHOULD NOT BE USED DURING PREGNANCY. Reclast may cause fetal harm when administered to a
`pregnant woman. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential
`harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while on Reclast
`therapy [see Use in Specific Populations (8.1)].
`5.7 Musculoskeletal Pain
`In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been
`infrequently reported in patients taking bisphosphonates, including Reclast. The time to onset of symptoms varied from
`one day to several months after starting the drug. Consider withholding future Reclast treatment if severe symptoms
`develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged
`with the same drug or another bisphosphonate [see Adverse Reactions (6.2)].
`5.8 Patients with Asthma
`While not observed in clinical trials with Reclast, there have been reports of bronchoconstriction in aspirin-sensitive
`patients receiving bisphosphonates. Use Reclast with caution in aspirin-sensitive patients.
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
`of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
`in practice.
`Treatment of Osteoporosis in Postmenopausal Women
`The safety of Reclast in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized,
`double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65-89 years with
`osteoporosis, diagnosed by bone mineral density or the presence of a prevalent vertebral fracture. The duration of the trial
`was three years with 3862 patients exposed to Reclast and 3852 patients exposed to placebo administered once annually
`as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received
`1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplementation per day.
`The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast group and 2.9% in the placebo
`group. The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group. The
`percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo
`groups, respectively.
`The safety of Reclast in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was
`assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men
`and women aged 50-95 years; 1065 patients were randomized to Reclast and 1062 patients were randomized to placebo.
`Reclast was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The
`study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for
`an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of
`
`Reference ID: 3008875
`
`

`

`
`vitamin D (50,000 to 125,000 IU orally or IM) was given to patients and they were started on 1000 to 1500 mg of
`elemental calcium plus 800 to 1200 IU of vitamin D supplementation per day for at least 14 days prior to the study drug
`infusions.
`The incidence of all-cause mortality was 9.6% in the Reclast group and 13.3% in the placebo group. The incidence of
`serious adverse events was 38.3% in the Reclast group and 41.3% in the placebo group. The percentage of patients who
`withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast and placebo groups, respectively.
`Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast-treated patients
`than placebo-treated patients in either osteoporosis trial are shown below in Table 1.
`Table 1. Adverse Reactions Occurring in ≥ 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-Treated Patients
`
`
`
`
`
`System Organ Class
`
`
`
`
`
`Reference ID: 3008875
`
`Study 1
`
`5 mg IV
`Reclast
`once per year
`%
`(N=3862)
`
`
`Placebo
`once per year
`%
`(N=3852)
`
`4.4
`
`0.6
`2.0
`
`12.4
`7.6
`
`4.3
`
`2.4
`
`12.7
`
`8.5
`6.0
`4.6
`4.6
`4.3
`
`23.8
`11.7
`11.3
`6.9
`5.8
`4.4
`3.7
`9.1
`0.4
`
`17.9
`8.8
`5.4
`5.4
`5.3
`4.6
`3.3
`2.0
`0.3
`1.3
`
`2.0
`
`3.6
`
`0.6
`1.1
`
`8.1
`6.7
`
`4.0
`
`1.9
`
`12.4
`
`5.2
`5.6
`3.2
`3.1
`4.0
`
`20.4
`3.7
`9.9
`5.6
`2.3
`3.8
`3.4
`9.7
`0.3
`
`4.6
`2.7
`3.5
`1.0
`2.9
`4.2
`1.3
`1.0
`<0.1
`1.1
`
`2.4
`
`
`
`
`
`5.3
`
`2.5
`1.0
`
`3.9
`2.0
`
`1.3
`
` 2.8
`
`6.8
`
`4.5
`5.2
`3.4
`0.9
`1.7
`
`17.9
`4.9
`5.9
`0.0
`3.2
`1.4
`1.5
`5.7
`3.1
`
`8.7
`0.8
`2.1
`1.5
`3.2
`5.5
`1.5
`1.1
`2.3
`2.4
`
`2.1
`
`Blood and the Lymphatic System Disorders
` Anemia
`Metabolism and Nutrition Disorders
` Dehydration
` Anorexia
`Nervous System Disorders
` Headache
` Dizziness
`Ear and Labyrinth Disorders
` Vertigo
`Cardiac Disorders
` Atrial Fibrillation
`Vascular Disorders
` Hypertension
`Gastrointestinal Diso