TERIPARATIDE

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 C 181 H 291 N 55 O 51 S 2 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 volume to allow delivery of 2.24 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. Each device contains additional volume to allow troubleshooting of the device 2 times. Structure

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. 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)

Recommended dosage is 20 mcg subcutaneously once a day ( 2.1 ) Consider supplemental calcium and Vitamin D based on individual patient needs (2.1) Administer as a subcutaneous injection into the thigh or abdominal region (2.2) Administer initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur (2.2) Use of teriparatide for more than 2 years during a patient’s lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture (2.3) 2.1 Recommended Dosage The recommended dosage is 20 mcg per dose given subcutaneously once a day. Instruct patients to take supplemental calcium and vitamin D if daily dietary intake is inadequate. 2.2 Administration Instructions Administer teriparatide as a subcutaneous injection into the thigh or abdominal region. Teriparatide is not approved for intravenous or intramuscular use. Teriparatide injection should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur [see Warnings and Precautions ( 5.4 )]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. (Teriparatide injection is a clear and colorless liquid). Do not use if solid particles appear or if the solution is cloudy or colored. Patients and/or caregivers who administer teriparatide injection should receive appropriate training and instruction on the proper use of the teriparatide injection prefilled delivery device (pen) from a qualified health professional. Discard the delivery device 28 days after first use. 2.3 Recommended Treatment Duration Use of teriparatide injection for more than 2 years during a patient’s lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture [see Warnings and Precautions ( 5.1 )].

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)]. Patients with hypersensitivity to teriparatide or to any of its excipients ( 4 )

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 . 6.1 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 1,000 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-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-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality Teriparatide Injection N=691 Placebo N=691 Event Classification (%) (%) Body as a Whole Pain 21.3 20.5 Headache 7.5 7.4 Asthenia 8.7 6.8 Neck pain 3.0 2.7 Cardiovascular Hypertension 7.1 6.8 Angina pectoris 2.5 1.6 Syncope 2.6 1.4 Digestive System Nausea 8.5 6.7 Constipation 5.4 4.5 Diarrhea 5.1 4.6 Dyspepsia 5.2 4.1 Vomiting 3.0 2.3 Gastrointestinal disorder 2.3 2.0 Tooth disorder 2.0 1.3 Musculoskeletal Arthralgia 10.1 8.4 Leg cramps 2.6 1.3 Nervous System Dizziness 8.0 5.4 Depression 4.1 2.7 Insomnia 4.3 3.6 Vertigo 3.8 2.7 Respiratory System Rhinitis 9.6 8.8 Cough increased 6.4 5.5 Pharyngitis 5.5 4.8 Dyspnea 3.6 2.6 Pneumonia 3.9 3.3 Skin and Appendages Rash 4.9 4.5 Sweating 2.2 1.7 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 1,000 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-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.

Digoxin: Transient hypercalcemia may predispose patients to digitalis toxicity (5.5, 7.1 ) 7.1 Digoxin Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide injection may transiently increase serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when teriparatide injection is used in patients receiving digoxin [see Warnings and Precaution (5.5) and Clinical Pharmacology ( 12.3 )].

16.2 Storage and Handling Store teriparatide injection, USP under refrigeration at 2°C to 8°C (36°F to 46°F) at all times except when administering the product. Recap the delivery device (pen) when not in use to protect the cartridge from physical damage and light. When using teriparatide injection, minimize the time out of the refrigerator; deliver the dose immediately following removal from the refrigerator. Do not freeze. Do not use teriparatide injection, USP if it has been frozen. Throw away the device 28 days after first use.