`
`
`
`
`
`
`
`
` 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
`-------------------------------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)
`
`
`Limitations of Use
`Optimal duration of use has not been determined. For patients at low-risk for
`
`
`
`
`fracture, consider drug discontinuation after 3 to 5 years of use (1.6)
`
`
`
`
`
`----------------------------DOSAGE AND ADMINISTRATION--------------------­
`Infusion given intravenously over no less than 15 minutes:
`
`
`
`• Treatment of postmenopausal osteoporosis (2.2); treatment to increase bone
`
`
`
`
`
`mass in men with osteoporosis (2.4): treatment and prevention of glucocorticoid­
`
`
`
`induced osteoporosis (2.5): 5 mg once a year
`
`• Prevention of postmenopausal osteoporosis: 5 mg once every 2 years (2.3)
`
`
`
`
`• Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should
`
`
`
`
`receive 1500 mg elemental calcium and 800 international units vitamin D daily
`
`
`
`
`
`(2.6)
`--------------------------DOSAGE FORMS AND STRENGTHS--------------------­
`5 mg in a 100 mL ready-to-infuse solution (3)
`
`
`------------------------------------CONTRAINDICATIONS---------------------------­
`• Hypocalcemia (4)
`
`
`• Patients with creatinine clearance less than 35 mL/min and in those with
`
`
`
`
`evidence of acute renal impairment (4, 5.3)
`
`
`• Hypersensitivity to any component of Reclast (4, 6.2)
`
`
`---------------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• Products Containing Same Active Ingredient: Patients receiving Zometa
`
`
`
`should not receive Reclast (5.1)
`
`
`
`
`
`
`
`
`
`
`
`• Hypocalcemia may worsen during treatment. Patients must be adequately
`
`
`
`
`
`
`supplemented with calcium and vitamin D (5.2)
`• Renal Impairment: 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 (2.7,
`
`5.3)
`
`
`
`• Osteonecrosis of the Jaw (ONJ) 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)
`• Pregnancy: Reclast can cause fetal harm. Women of childbearing potential
`
`
`
`
`
`should be advised (5.6, 8.1)
`• Severe Bone, Joint, and Muscle Pain may occur. Withhold future doses of
`
`
`
`
`
`Reclast if severe symptoms occur (5.7)
`------------------------------------ADVERSE REACTIONS----------------------------­
`
`
`
`The most common adverse reactions (greater than 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 Medication
`
`Guide
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 7/2017
`
`
`
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`Treatment of Osteoporosis in Postmenopausal Women
`1.1
`
`
`Prevention of Osteoporosis in Postmenopausal Women
`1.2
`
`
`
`1.3 Osteoporosis in Men
`
`
`1.4 Glucocorticoid-Induced Osteoporosis
`
`
`1.5
`Paget's Disease of Bone
`
`
`1.6
`Important Limitations of Use
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Important Administration Instructions
`
`
`Treatment of Osteoporosis in Postmenopausal Women
`2.2
`
`
`2.3
`Prevention of Osteoporosis in Postmenopausal Women
`
`
`2.4 Osteoporosis in Men
`
`
`2.5
`Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
`
`
`
`2.6
`Treatment of Paget’s Disease of Bone
`
`
`2.7
`Laboratory Testing and Oral Examination Prior to Administration
`
`
`
`2.8 Calcium and Vitamin D Supplementation
`
`
`
`2.9 Method of Administration
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`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
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`Post-Marketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`6
`
`
`7
`
`
`
`
`8
`
`
`
`7.1 Aminoglycosides
`
`
`7.2
`Loop Diuretics
`
`
`7.3 Nephrotoxic Drugs
`
`
`7.4 Drugs Primarily Excreted by the Kidney
`
`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
`
`
`
`
`Reference ID: 4121283
`
`ANTECIP EXHIBIT 2024
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2018-00001
`
`Page 1
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`
`
`
` 1
`
`
`
`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)].
`
`
`
`
`
`Prevention of Osteoporosis in Postmenopausal Women
`1.2
`Reclast is indicated for prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.2)].
`
`
`
`
`Osteoporosis in Men
`1.3
`Reclast is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3)].
`
`
`
`
`
`
`
`Glucocorticoid-Induced Osteoporosis
`1.4
`
`
`
`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)].
`
`
`
`
`
`
`
`
`Paget's Disease of Bone
`1.5
`
`
`
`
`
`
`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)].
`
`
`
`Important Limitations of Use
`1.6
`
`
`
`
`
`
`
`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. Patients at low-risk for fracture should be considered for drug
`
`
`
`
`discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated
`
`periodically.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1
`Important Administration Instructions
`
`
`
`
`Reclast injection must be administered as an intravenous infusion over no less than 15 minutes.
`
`• Patients must be appropriately hydrated prior to administration of Reclast [see Warnings and Precautions (5.3)].
`
`
`
`
`• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`
`whenever solution and container permit.
`
`
`
`
`
`Intravenous 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.
`
`
` Treatment of Osteoporosis in Postmenopausal Women
`
`2.2
` The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.
`
` Prevention of Osteoporosis in Postmenopausal Women
`
`
`2.3
` The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes.
`
`
`
`2.4
`Osteoporosis in Men
`
`
`
`The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.
`
`
`
`Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
`2.5
`
`
`The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4121283
`
`Page 2
`
`

`

`
`
`
`2.8
`
`•
`
` 2.6
`
`
`
` 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.
`
`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.
`
`
`
`
`2.7
`Laboratory Testing and Oral Examination Prior to Administration
`
`
`
`
`
`
`
`• Prior to administration of each dose of Reclast, obtain a serum creatinine and creatinine clearance should be
`
`
`
`
`
`calculated based on actual body weight using Cockcroft-Gault formula before each Reclast dose. Reclast is
`
`
`
`
`
`contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal
`
`
`impairment. A 5 mg dose of Reclast administered intravenously is recommended for patients with creatinine
`
`
`
`
`
`
`clearance greater than or equal to 35 mL/min. 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 greater
`
`than or equal to 35 mL/min [see Contraindications (4), Warnings and Precautions (5.3)].
`
`
`
`
`
`• A routine oral examination should be performed by the prescriber prior to initiation of Reclast treatment [see
`
`
`
`
`
`Warnings and Precautions (5.4)].
`
`
`Calcium and Vitamin D Supplementation
`
`
`
`Instruct patients being treated for Paget’s disease of bone on the importance of calcium and vitamin D
`
`
`supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. All patients should take
`
`
`
`1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800
`
`international units vitamin D daily, particularly in the 2 weeks following Reclast administration [see Warnings and
`
`
`
`
`
`Precautions (5.2)].
`
`
`
`
`
`Instruct patients being treated for osteoporosis to take supplemental calcium and vitamin D if their dietary intake is
`
`
`
`inadequate. An average of at least 1200 mg calcium and 800-1000 international units vitamin D daily is
`
`recommended.
`
`
`2.9 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.
`
`
`CONTRAINDICATIONS
`4
`
`
`
`Reclast is contraindicated in patients with the following conditions:
`• Hypocalcemia [see Warnings and Precautions (5.2)]
`
`
`
`
`
`
`
`
`• Creatinine clearance less than 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)].
`
`
`
`
`
`
`
`
`
`
`• Known hypersensitivity to zoledronic acid or any components of Reclast. Hypersensitivity reactions including
`
`urticaria, angioedema, and anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)].
`
`
`
`•
`
`Reference ID: 4121283
`
`Page 3
`
`

`

`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`
`Drug Products with Same Active Ingredient
`5.1
`
`
`
`
`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.
`
`
`
`Hypocalcemia and Mineral Metabolism
`5.2
`
`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 (2.8), Adverse Reactions (6.1), Patient Counseling Information (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 (2.8), Adverse Reactions (6.1), Patient Counseling Information
`(17)].
`
`
`
`Renal Impairment
`5.3
`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)].
`
`
`
`
`
`Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute
`renal impairment [see Contraindications (4)]. If history or physical signs suggest dehydration, Reclast therapy should be
`
`
`
`
`
`withheld until normovolemic status has been achieved [see Adverse Reactions (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 Adverse Reactions (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, angiogenesis inhibitors, radiotherapy,
`
`corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy). The risk of ONJ may
`
` increase with duration of exposure to bisphosphonates. Concomitant administration of drugs associated with ONJ may
`
`
`
`
` increase the risk of developing ONJ.
`
`
`
`
`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: 4121283
`
`Page 4
`
`

`

`
`
` 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.
`
`
`Pregnancy
`5.6
`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)].
`
`
`Patients with Asthma
`5.8
`
`
`
`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 Trials 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 to 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 international units 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 to 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
`
`
`vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500
`Reference ID: 4121283
`
`Page 5
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`

`

`
`
`
`
`
`
`
`
`
`
` mg of elemental calcium plus 800 to 1200 international units 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 greater than or equal to 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-
`
`
` Treated Patients
`
`
` Study 2
` 5 mg IV
`
`
` Reclast
`once per year
`
`%
` (N=1054)
`
`
`Placebo
`
` once per year
`
`%
` (N=1057)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`System Organ Class
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 Disorders
`
`
` Nausea
`
`
` Diarrhea
`
`
` Vomiting
` Abdominal Pain Upper
`
`
`
` Dyspepsia
` Musculoskeletal, Connective Tissue and Bone Disorders
`
`
` Arthralgia
`
` Myalgia
`
`
` Pain in Extremity
`
` Shoulder Pain
`
`
`
` Bone Pain
`
`
` Neck Pain
`
` Muscle Spasms
`
`
` Osteoarthritis
`
`
` Musculoskeletal Pain
` General Disorders and Administrative Site Conditions
`
`
`
` Pyrexia
`
` Influenza-like Illness
`
` Fatigue
`
`
`
` Chills
`
`
` Asthenia
`
` Peripheral Edema
`
` Pain
`
`
`
` Malaise
` Hyperthermia
`
`
`
` Chest Pain
` Investigations
`
`
` Creatinine Renal Clearance Decreased
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4121283
`
`
`
`
`
`
`
` Study 1
`
`
` 5 mg IV
`
` Reclast
`once per year
`
`%
` (N=3862)
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`Placebo
`
` once per year
`
`%
` (N=3852)
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
` 5.2
`
`
` 2.3
`
` 1.0
`
`
` 2.5
`
` 4.0
`
`
` 1.7
`
`
` 2.6
`
`
` 5.4
`
`
` 4.5
`
` 4.7
`
` 3.4
`
` 1.5
`
` 1.6
`
` 18.3
`
` 2.7
`
`
` 4.8
`
` 0.0
`
` 1.0
`
` 1.1
`
` 1.7
`
` 4.5
`
` 1.2
`
`
` 3.1
`
` 0.4
`
` 1.2
`
` 0.5
`
` 3.0
`
` 5.3
`
` 0.5
`
` 0.5
`
` 0.3
`
` 1.8
`
` 1.7
`
`
`
`Page 6
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`

`

`
`
`
`
` Renal Impairment
`
` Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment
`
`
`
`
`
`
` manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. In the
`
`
`
`
`
`
`clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance less than 30 mL/min (based on
`
`
`
`
`
`actual body weight), urine dipstick greater than or equal to 2+ protein or increase in serum creatinine of greater than 0.5
`
`
`mg/dL during the screening visits were excluded. The change in creatinine clearance (measured annually prior to dosing)
`
`
`
`
`
`and the incidence of renal failure and impairment was comparable for both the Reclast and placebo treatment groups over
`
`
`
`
`3 years, including patients with creatinine clearance between 30-60 mL/min at baseline. Overall, there was a transient
`
`
`
`increase in serum creatinine observed within 10 days of dosing in 1.8% of Reclast-treated patients versus 0.8% of
`
`placebo-treated patients which resolved without specific therapy [see Warnings and Precautions (5.3)].
`
`
`
`Acute Phase Reaction
`The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast infusion including fever (18%),
`
`
`
`
`myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred
`
`
`
`within the first 3 days following the dose of Reclast and usually resolved within 3 days of onset but resolution could take
`
`
`
`up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose
`
`
`at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed.
`
`
`
`
`
`
`
`Reclast was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and
`
`
`
`
`arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast.
`
`
`Laboratory Findings
`
`
`
`
`
`In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum
`
`calcium levels (less than 7.5 mg/dL) following Reclast administration. No symptomatic cases of hypocalcemia were
`observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels
`
`below 7.5 mg/dL.
`
`Injection Site Reactions
`
`
`
`
`
`In the osteoporosis trials, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0%
`
`
`
`to 0.7% of patients following the administration of Reclast and 0% to 0.5% of patients following administration of
`
`placebo.
`
`
`Osteonecrosis of the Jaw
`
`
`
`
`In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with
`
`
`ONJ occurred in one patient treated with placebo and one patient treated with Reclast. Both cases resolved after
`
`
`appropriate treatment [see Warnings and Precautions (5.4)]. No reports of osteonecrosis of the jaw were reported in either
`
`
`
`
`treatment group in Study 2.
`
`Atrial Fibrillation
`
`
`
`
`
`In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic
`
`
`
`
`acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo
`
`
`
`
`
`
`group. The overall incidence of all atrial fibrillation adverse events in t