Teriparatide

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. Teriparatide injection is a synthetic 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 )

2 DOSAGE AND ADMINISTRATION 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 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 ( 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 injection as a subcutaneous injection into the thigh or abdominal region.Teriparatide injection 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 ) ] .

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

5 WARNINGS AND PRECAUTIONS Osteosarcoma : Avoid use in patients with increased risk of osteosarcoma including patients with open epiphyses, metabolic bone diseases including Paget’s disease, bone metastases or history of skeletal malignancies, prior external beam or implant radiation therapy involving the skeleton, and hereditary disorders predisposing to osteosarcoma. ( 5.1 ) Hypercalcemia and Cutaneous Calcification : Avoid in patients known to have an underlying hypercalcemic disorder. Discontinue in patients developing worsening of previously stable cutaneous calcification. ( 5.2 ) Risk of Urolithiasis : Consider the risk/benefit in patients with active or recent urolithiasis because of risk of exacerbation ( 5.3 ) Orthostatic Hypotension : Transient orthostatic hypotension may occur with initial doses of Teriparatide injection ( 5.4 ) 5.1 Osteosarcoma An increase in the incidence of osteosarcoma (a malignant bone tumor) was observed in male and female rats treated with teriparatide. Osteosarcoma has been reported in patients treated with Teriparatide injection in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of Teriparatide injection use [ see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.3 ), and Nonclinical Toxicology ( 13.1 ) ] . Avoid Teriparatide injection use in patients with (these patients are at increased baseline risk of osteosarcoma): Open epiphyses (pediatric and young adult patients) (Teriparatide injection is not approved in pediatric patients) [ see Use in Specific Populations ( 8.4 ) ]. Metabolic bone diseases other than osteoporosis, including Paget’s disease of the bone. Bone metastases or a history of skeletal malignancies. Prior external beam or implant radiation therapy involving the skeleton. Hereditary disorders predisposing to osteosarcoma. 5.2 Hypercalcemia and Cutaneous Calcification Hypercalcemia Teriparatide injection has not been studied in patients with pre-existing hypercalcemia. Teriparatide injection may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia [ see Adverse Reactions ( 6.1 , 6.3 ) ] . Avoid Teriparatide injection in patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism. Risk of Cutaneous Calcification Including Calciphylaxis Serious reports of calciphylaxis and worsening of previously stable cutaneous calcification have been reported in the postmarketing setting in patients taking Teriparatide injection. Risk factors for development of calciphylaxis include underlying autoimmune disease, kidney failure, and concomitant warfarin or systemic corticosteroid use. Discontinue Teriparatide injection in patients who develop calciphylaxis or worsening of previously stable cutaneous calcification. 5.3 Risk of Urolithiasis In clinical trials, the frequency of urolithiasis was similar in patients treated with Teriparatide injection and patients treated with placebo. However, Teriparatide injection has not been studied in patients with active urolithiasis. If Teriparatide injection-treated patients have pre-existing hypercalciuria or suspected/known active urolithiasis, consider measuring urinary calcium excretion. Consider the risks and benefits of use in patients with active or recent urolithiasis because of the potential to exacerbate this condition. 5.4 Orthostatic Hypotension Teriparatide injection should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies of Teriparatide injection in healthy volunteers, transient episodes of symptomatic orthostatic hypotension were observed in 5% of volunteers. Typically, these events began within 4 hours of dosing and resolved (without treatment) within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, it was relieved by placing the person in a reclining position, and it did not preclude continued treatment. 5.5 Risk of Digoxin Toxicity Hypercalcemia may predispose patients to digitalis toxicity because Teriparatide injection transiently increases serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when Teriparatide injection is used in patients receiving digoxin [ see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ) ] .

7 DRUG INTERACTIONS 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 ) ].

6 ADVERSE REACTIONS Most common adverse reactions (>10%) include: arthralgia, pain, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 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 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 injection-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 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 injection 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 injection-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 ≥ 5mg 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 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 injection 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 injection. 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 injection-treated patients. In these two studies, three and zero osteosarcoma cases were identified among 379,283 and 153,316 Teriparatide injection users, respectively. The study results suggest a similar risk for osteosarcoma between Teriparatide injection 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.

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/m 2 ), 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/m 2 ). 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.