PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - Injection delivery device label

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 600 mcg/2.4 mL

APOTEX CORP.

Teriparatide Injection, USP

NDC 60505-6188-0

20 mcg per dose

Rx

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DESCRIPTION SECTION

11 DESCRIPTION

Teriparatide injection, USP contains chemically synthesized human parathyroid hormone (1-34), and is also called hPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.

The molecular formula of teriparatide is C181H291N55O51S2 and a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

Teriparatide is manufactured chemical synthesis. Teriparatide injection, USP is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

Each prefilled delivery device (pen) delivers 20 mcg of teriparatide per dose for up to 28 days.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high- affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.

The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.

12.2 Pharmacodynamics

Pharmacodynamics in Men with Primary or Hypogonadal Osteoporosis and Postmenopausal Women with Osteoporosis

Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).

Serum Calcium Concentrations — When teriparatide 20 mcg was administered once daily, the serum calcium concentration increased transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL). The serum calcium concentration began to decline approximately 6 hours after dosing and returned to baseline by 16 to 24 hours after each dose.

In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide injection (20 mcg subcutaneous once daily) was 9.68 mg/dL at 12 months. The peak serum calcium remained below 11 mg/dL in >99% of women at each visit. Sustained hypercalcemia was not observed.

In this study, 11.1% of women treated with teriparatide injection had at least 1 serum calcium value above the upper limit of normal (ULN) (10.6 mg/dL) compared with 1.5% of women treated with placebo. The percentage of women treated with teriparatide injection whose serum calcium was above the ULN on consecutive 4- to 6-hour post-dose measurements was 3% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or teriparatide injection doses were reduced. The timing of these dose reductions was at the discretion of the investigator. Teriparatide injection dose adjustments were made at varying intervals after the first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive increases in serum calcium.

In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide injection was 9.44 mg/dL at 12 months. The peak serum calcium remained below 11 mg/dL in 98% of men at each visit. Sustained hypercalcemia was not observed. In this study, 6% of men treated with teriparatide injection daily had at least 1 serum calcium value above the ULN (10.6 mg/dL) compared with none of the men treated with placebo. The percentage of men treated with teriparatide injection whose serum calcium was above the ULN on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Calcium supplementation was reduced in these men [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum calcium >12 hours after teriparatide injection treatment was increased by 0.36 to 0.56 mg/dL, after 1 to 6 months of teriparatide injection treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >11 mg/dL, and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >11.mg/dL. The highest serum calcium reported was 12.5 mg/dL. None of the women had symptoms of hypercalcemia. There were no placebo controls in this study.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide injection on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide injection increased urinary calcium excretion. The median urinary excretion of calcium was 190 mg/day at 6 months and 170 mg/day at 12 months. These levels were 30 mg/day and 12 mg/day higher, respectively, than in women treated with placebo. The incidence of hypercalciuria (>300 mg/day) was similar in the women treated with teriparatide injection or placebo.

In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide injection had inconsistent effects on urinary calcium excretion. The median urinary excretion of calcium was 220 mg/day at 1 month and 210 mg/day at 6 months. These levels were 20 mg/day higher and 8 mg/day lower, respectively, than in men treated with placebo. The incidence of hypercalciuria (>300 mg/day) was similar in the men treated with teriparatide injection or placebo.

Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia (<2.4 mg/dL) was not observed in clinical trials with teriparatide injection.

In clinical trials of daily teriparatide injection, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide injection on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Effects on Markers of Bone Turnover — Daily administration of teriparatide injection to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in men.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide injection on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

12.3 Pharmacokinetics

Absorption — Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80- mcg doses (1-, 2-, and 4-times the recommended dosage, respectively). The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.

Distribution — Volume of distribution following intravenous injection is approximately 0.12 L/kg.

Elimination — Systemic clearance of teriparatide (approximately 62 L/hour in women and 94 L/hour in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. The half-life of teriparatide in serum was approximately 1 hour when administered by subcutaneous injection. No metabolism or excretion studies have been performed with teriparatide. Peripheral metabolism of PTH is believed to occur by non- specific enzymatic mechanisms in the liver followed by excretion via the kidneys.

Specific Populations

Geriatric Patients — No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years).

Male and Female Patients — Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dosage for men and women is the same.

Racial Groups —The influence of race has not been determined.

Patients with Renal Impairment — No pharmacokinetic differences were identified in 11 patients with creatinine clearance (CrCl) 30 to 72 mL/minute administered a single dose of teriparatide. In 5 patients with severe renal impairment (CrCl<30 mL/minute), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure.

Patients with Hepatic Impairment — No studies have been performed in patients with hepatic impairment. Non-specific proteolytic enzymes in the liver (possibly Kupffer cells) cleave PTH(1-34) and PTH(1-84) into fragments that are cleared from the circulation mainly by the kidney.

Drug Interaction Studies

Digoxin — In a study of 15 healthy people administered digoxin daily to steady state, a single teriparatide injection dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin’s calcium-mediated cardiac effect).

Hydrochlorothiazide — In a study of 20 healthy people, the coadministration of hydrochlorothiazide 25 mg with 40 mcg of teriparatide (2 times the recommended dose) did not affect the serum calcium response to teriparatide injection. The 24-hour urine excretion of calcium was reduced by a clinically unimportant amount (15%). The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied.

Furosemide — In a study of 9 healthy people and 17 patients with CrCl 13 to 72 mL/minute, coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg (2 times the recommended dose) resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%); however, these changes did not appear to be clinically important.

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INDICATIONS & USAGE SECTION

Highlight: Teriparatide injection is a parathyroid hormone analog, (PTH 1-34), indicated for:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy (1)
• Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy (1)
• Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy (1)

1 INDICATIONS AND USAGE

Teriparatide injection is indicated.

• For the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined herein as having a history of osteoporotic fracture or multiple risk factors for fracture) or who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, teriparatide injection reduces the risk of vertebral and nonvertebral fractures.
• To increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy.
• For the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection: 600 mcg/2.4 mL (250 mcg/mL) in a single-patient-use prefilled delivery device (pen) containing 28 daily doses of 20 mcg (3)

3 DOSAGE FORMS AND STRENGTHS

Injection: 600 mcg/2.4 mL (250 mcg/mL) clear, colorless solution in a single- patient-use prefilled delivery device (pen) containing 28 daily doses of 20 mcg.

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CONTRAINDICATIONS SECTION

Highlight: * Patients with hypersensitivity to teriparatide or to any of its excipients (4)

4 CONTRAINDICATIONS

Teriparatide injection is contraindicated in patients with hypersensitivity to teriparatide or to any of its excipients. Hypersensitivity reactions have included angioedema and anaphylaxis [see Adverse Reactions (6.3)].

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: Consider discontinuing when pregnancy is recognized (8.1)

• Lactation: Breastfeeding is not recommended (8.2)
• Pediatric Use: Safety and effectiveness not established. Avoid use due to increased baseline risk of osteosarcoma (5.1, 8.4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on teriparatide injection use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider discontinuing teriparatide injection when pregnancy is recognized.

In animal reproduction studies, teriparatide increased skeletal deviations and variations in mouse offspring at subcutaneous doses equivalent to more than 60 times the recommended 20 mcg human daily dose (based on body surface area, mcg/m2), and produced mild growth retardation and reduced motor activity in rat offspring at subcutaneous doses equivalent to more than 120 times the human dose (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In animal reproduction studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses equivalent to 8 to 267 times the human dose (based on body surface area, mcg/m2). At subcutaneous doses ≥60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received teriparatide during organogenesis at subcutaneous doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.

In a perinatal/postnatal study in pregnant rats dosed subcutaneously from organogenesis through lactation, mild growth retardation was observed in female offspring at doses ≥120 times the human dose. Mild growth retardation in male offspring and reduced motor activity in both male and female offspring were observed at maternal doses of 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.

8.2 Lactation

Risk Summary

It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breastfed infant. Avoid teriparatide use in women who are breastfeeding.

8.4 Pediatric Use

The safety and effectiveness of teriparatide injection have not been established in pediatric patients. Pediatric patients are at higher baseline risk of osteosarcoma because of open epiphyses [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Of the patients who received teriparatide injection in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and older and 23% were 75 years of age and older. Of the patients who received teriparatide injection in the trial of 437 men with primary or hypogonadal osteoporosis, 39% were 65 years of age and over and 13% were 75 years of age and over. Of the 214 patients who received teriparatide injection in the glucocorticoid induced osteoporosis trial, 28% were 65 years of age and older and 9% were 75 years of age and older. No overall differences in safety or effectiveness of teriparatide injection have been observed between patients 65 years of age and older and younger adult patients.

8.6 Hepatic Impairment

No studies have been performed in patients with hepatic impairment. [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

In 5 patients with severe renal impairment (CrCl<30 mL/minute), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. It is unknown whether teriparatide injection alters the underlying metabolic bone disease seen in chronic renal impairment [see Clinical Pharmacology (12.3)].

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (>10%) include: arthralgia, pain, and nausea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Inc. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or** www.fda.gov/medwatch**.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Men with Primary or Hypogonadal Osteoporosis and Postmenopausal Women with Osteoporosis

The safety of teriparatide injection in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, double-blind, placebo-controlled trials of 1382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years) [see Clinical Studies (14.1, 14.2)]. The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to teriparatide injection and 691 patients to placebo. All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was 1% in the teriparatide injection group and 1% in the placebo group. The incidence of serious adverse events was 16% in the teriparatide injection group and 19% in the placebo group. Early discontinuation due to adverse events occurred in 7% in the teriparatide injection group and 6% in the placebo group.

Table 1 lists adverse events from these two trials that occurred in ≥2% of teriparatide injection-treated and more frequently than placebo-treated patients.

Table 1. Percentage of Patients with Adverse Events Reported by at Least 2% of Teriparatide Treated Patients and in More Teriparatide Injection- Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality

Laboratory Findings

Serum Calcium — Teriparatide injection transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after teriparatide injection administration was 11% of women and 6% of men treated with teriparatide compared to 2% of women and 0% of the men treated with placebo. The percentage of patients treated with teriparatide injection whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.

Urinary Calcium — Teriparatide injection increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with teriparatide injection and placebo [see Clinical Pharmacology (12.2)].

Serum Uric Acid — Teriparatide injection increased serum uric acid concentrations. In clinical trials, 3% of teriparatide -treated patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo-treated patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.

Renal Function — No clinically important adverse renal effects were observed in clinical studies. Assessments included creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; and examination of urine sediment.

Men and Women with Glucocorticoid-Induced Osteoporosis

The safety of teriparatide injection in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a randomized, double- blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥5 mg per day prednisone or equivalent for a minimum of 3 months [see Clinical Studies (14.3)]. The duration of the trial was 18 months with 214 patients exposed to teriparatide injection and 214 patients exposed to an oral daily bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.

There was no increase in mortality in the teriparatide group compared to the active control group. The incidence of serious adverse events was 21% in teriparatide injection patients and 18% in active control patients, and included pneumonia (3% teriparatide injection, 1% active control). Early discontinuation because of adverse events occurred in 15% of teriparatide injection patients and 12% of active control patients, and included dizziness (2% teriparatide injection, 0% active control).

Adverse events reported at a higher incidence in the teriparatide injection group and with at least a 2% difference in teriparatide injection-treated patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively.

6.2 Immunogenicity

As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other teriparatide products may be misleading.

In the clinical trial of postmenopausal women with osteoporosis [see Clinical Studies (14.1)], antibodies that cross reacted with teriparatide were detected in 3% of women (15/541) who received teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.

6.3 Postmarketing Experience

Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during postapproval use of teriparatide injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period [see Warnings and Precautions (5.2)].
• Hypercalcemia greater than 13 mg/dL has been reported with teriparatide injection use.

Adverse events reported since market introduction that were temporally related to teriparatide injection therapy include the following:

• Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria
• Investigations: Hyperuricemia
• Respiratory System: Acute dyspnea, chest pain
• Musculoskeletal: Muscle spasms of the leg or back
• Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema

Adverse Reactions from Observational Studies to Assess Incidence of Osteosarcoma

Two osteosarcoma surveillance safety studies (U.S. claims-based database studies) were designed to obtain data on the incidence rate of osteosarcoma among teriparatide-treated patients. In these two studies, three and zero osteosarcoma cases were identified among 379,283 and 153,316 teriparatide users, respectively. The study results suggest a similar risk for osteosarcoma between teriparatide users and their comparators. However, the interpretation of the study results calls for caution owing to the limitations of the data sources which do not allow for complete measurement and control for confounders.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in rat systemic exposures that were 3, 20, and 60 times higher than the systemic exposure observed in humans, respectively, following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose- related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.

The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous teriparatide doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, respectively, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of teriparatide exposure. Bone tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day of teriparatide for 24 months or with 5 or 30 mcg/kg/day of teriparatide for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day of teriparatide for 6 or 20 months. Tumors were not detected when mature 6-month old rats were treated with 5 mcg/kg/day of teriparatide for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.

No bone tumors were detected in a long-term monkey study [see Nonclinical Toxicology (13.2)].

Mutagenesis

Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.

Impairment of Fertility

No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).

13.2 Animal Toxicology

In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose based on surface area, mcg/m2).

In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study.

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SPL MEDGUIDE SECTION

** Medication Guide**

Teriparatide Injection**, USP**

(ter” i par’ a tide)

for subcutaneous use

Read this Medication Guide before you start using teriparatide injection and each time you get a refill. There may be new information. Also, read the User Manual that comes with the teriparatide injection delivery device (pen) for information on how to use the device to inject your medicine the right way. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about teriparatide injection?

**Possible bone cancer.**During drug testing, the medicine in teriparatide injection caused some rats to develop a bone cancer called osteosarcoma. Studies in people have not shown that teriparatide injection increases your chance of getting osteosarcoma. There is little information about the chance of getting osteosarcoma in patients using teriparatide injection beyond 2 years.

What is teriparatide injection?

Teriparatide injection is a prescription medicine used to:

• treat postmenopausal women who have osteoporosis who are at high risk for having broken bones (fractures) or who cannot use other osteoporosis treatments. Teriparatide injection can lessen the chance of broken bones (fractures) in the spine and other bones in postmenopausal women with osteoporosis.
• increase the bone mass in men with primary or hypogonadal osteoporosis who are at high risk for having broken bones (fractures) or who cannot use other osteoporosis treatments.
• treat both men and women with osteoporosis due to use of glucocorticoid medicines, such as prednisone, for several months, who are at high risk for having broken bones (fractures) or who cannot use other osteoporosis treatments.

It is not known if teriparatide injection is safe and effective in children.

Teriparatide injection should not be used in children and young adults whose bones are still growing.

Who should not use teriparatide injection?

Do not use teriparatide injection if you:

• are allergic to any of the ingredients in teriparatide injection. See the end of this Medication Guide for a complete list of the ingredients in teriparatide injection.

Symptoms of a serious allergic reaction of teriparatide injection may include swelling of the face, lips, tongue or throat that may cause difficulty in breathing or swallowing. Call your healthcare provider right away or get emergency medical help if you get any of these symptoms.

What should I tell my healthcare provider before using teriparatide injection?

Before you use teriparatide injection, tell your healthcare provider about all of your medical conditions, includingif you:

• have a certain bone disease called Paget’s disease or other bone disease.
• have bone cancer or have had a history of bone cancer.
• are a young adult whose bones are still growing.
• have had radiation therapy.
• are affected with a condition that runs in your family that can increase your chance of getting cancer in your bones.
• have or have had too much calcium in your blood (hypercalcemia).
• have or have had a skin condition with painful sores or wounds caused by too much calcium.
• have or have had kidney stones.
• take medicines that contain digoxin.
• are pregnant or plan to become pregnant. It is not known if teriparatide injection will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if teriparatide injection passes into your breastmilk. You should not breastfeed while taking teriparatide injection.

Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use teriparatide injection?

• Read the detailed Instructions for Use (User Manual) included with your teriparatide injection delivery device.
• Use teriparatide injection exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much teriparatide injection to use and when to use it.
• Before you try to inject teriparatide injection yourself, a healthcare provider should teach you how to use the teriparatide injection delivery device to give your injection the right way.
• Inject teriparatide injection 1 time each day in your thigh or abdomen (lower stomach area). Do not inject into a vein or a muscle. Talk to a healthcare provider about how to rotate injection sites.
• The teriparatide injection delivery device has enough medicine for 28 days. It is set to give a 20-microgram dose of medicine each day. Do not inject all the medicine in the teriparatide injection delivery device at any one time.
• Do not transfer the medicine from the teriparatide injection delivery device to a syringe. This can result in taking the wrong dose of teriparatide injection. If you do not have pen needles to use with your teriparatide injection delivery device, talk with your healthcare provider.
• Teriparatide injection should look clear and colorless. Do not use teriparatide injection if it has particles in it, or if it is cloudy or colored.
• Inject teriparatide injection right away after you take the delivery device out of the refrigerator.
• After each use, safely remove the needle, recap the delivery device, and put it back in the refrigerator right away.
• When you inject the first few doses of teriparatide injection, make sure you are in a place where you can sit or lie down right away in case you feel dizzy or have an abnormal heartbeat after the injection.
• Do not take more than 1 injection in the same day.
• Do not share your teriparatide injection delivery device with other people.
• If you take more teriparatide injection than prescribed, call your healthcare provider.
• If you take too much teriparatide injection, you may have nausea, vomiting, weakness, or dizziness.
• You should not use teriparatide injection for more than 2 years over your lifetime unless your healthcare provider finds that you need longer treatment because you have a high chance of breaking your bones.

If your healthcare provider recommends calcium and vitamin D supplements, you can take them at the same time you take teriparatide injection.

What are the possible side effects of teriparatide injection?

Teriparatide injection may cause serious side effects including:

• See “What is the most important information I should know about teriparatide injection?” ***Bone cancer (osteosarcoma):**Tell your healthcare provider right away if you have pain in your bones, pain in any areas of your body that does not go away, or any new or unusual lumps or swelling under your skin that is tender to touch. *Increased calcium in your blood. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood. *Worsening of your kidney stones. If you have or have had kidney stones your healthcare provider may check the calcium levels in your urine while you use teriparatide injection to see if there is worsening of this condition. ***Decrease in blood pressure when you change positions.**Some people may feel dizzy, get a fast heartbeat, or feel light-headed right after the first few doses of teriparatide injection. This usually happens within 4 hours of taking teriparatide injection and goes away within a few hours. For the first few doses, give your injections of teriparatide injection in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, contact your healthcare provider before you continue using teriparatide injection.

The most common side effects of teriparatide injection include:

• pain
• nausea
• joint aches

These are not all the possible side effects of teriparatide injection. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store teriparatide injection?

• Store teriparatide injection in the refrigerator between 36°F to 46°F (2°C to 8°C) until ready to use. Use teriparatide injection right away after you remove it from the refrigerator.
• Do not freeze the teriparatide injection delivery device. Do not use teriparatide injection if it has been frozen.
• Throw away the teriparatide injection delivery device after 28 days even if it has medicine in it (see the User Manual).
• Do not use teriparatide injection after the expiration date printed on the delivery device and packaging.
• Recap teriparatide injection when not in use to protect it from physical damage and light.

Keep teriparatide injection and all medicines out of the reach of children.

General information about the safe and effective use of teriparatide injection.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use teriparatide injection for a condition for which it was not prescribed. Do not give teriparatide injection to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about teriparatide injection that is written for health professionals.

What are the ingredients in teriparatide injection?

Active ingredient: teriparatide

Inactive ingredients: glacial acetic acid, sodium acetate (anhydrous), mannitol, metacresol, and water for injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

• All registered trademarks in this document are the property of their respective owners.

Medication Guide revised: January 2023

Marketed by: Apotex Corp. 2400 N. Commerce Parkway, Weston, FL 33326 U.S.A.

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INSTRUCTIONS FOR USE SECTION

Teriparatide Injection, USP

User Manual

Important: First read the Medication Guide that comes inside your teriparatide injection carton.

Before you use your newteriparatideinjection**** delivery device, please read the entire front and back of this User Manual completely. Follow the directions carefully when using the teriparatideinjection****** delivery device.**

Do not share your delivery device or needles because infection or disease can be spread from one person to another.

Theteriparatideinjection****** delivery device contains 28 days of medicine. Throw away theteriparatide injection delivery device after 28 days, even if it is not completely empty. Do not inject more than one dose of teriparatideinjection in the same day.**

Do not transferteriparatideinjection****** to a syringe.**

Wash your hands before every injection. Prepare the injection site as your healthcare provider instructed.

For more information, or if you have any questions, turn to the back of this page.

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