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 ) ] .

3 DOSAGE FORMS AND STRENGTHS Injection: 560 mcg/2.24 mL (250 mcg/mL) clear, colorless solution in a single-patient-use prefilled delivery device (pen) intended to deliver 28 daily doses of 20 mcg. Injection: 560 mcg/2.24 mL (250 mcg/mL) in a single-patient-use prefilled delivery device (pen) intended to deliver 28 daily doses of 20 mcg ( 3 )

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 )

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, arthralgi …

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 ) ].

8 USE IN SPECIFIC POPULATIONS 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 ) 8.1 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. 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 injection 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 T 1/2 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 ) ] .

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 micro-architecture 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.

11 DESCRIPTION Teriparatide injection is a synthetic parathyroid hormone analog (PTH 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 molecular weight is 4117.8 daltons. Its amino acid sequence is shown below: Teriparatide is manufactured using synthetic technology. Teriparatide injection is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a single-patient-use delivery device (pen) for subcutaneous injection. Each delivery device (pen) is filled with volume to allow delivery of 2.24 mL. Each mL contains 250 mcg of teriparatide (as a free base), 0.41 mg of glacial acetic acid, 0.1 mg of sodium acetate (anhydrous), 45.4 mg of mannitol, 3 mg of Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the pH to 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

10 OVERDOSAGE In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) (40 times the recommended dose) of the Teriparatide injection prefilled delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. No fatalities associated with overdose have been reported. Additional signs, symptoms, and complications of Teriparatide injection overdosage may include a delayed hypercalcemic effect, vomiting, dizziness, and headache. Overdose Management — There is no specific antidote for a Teriparatide injection overdose. Treatment of suspected overdose should include discontinuation of Teriparatide injection, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Teriparatide injection is a clear and colorless solution, available as single-patient-use prefilled delivery device (pen) in the following package size: 560 mcg/2.24 mL (250 mcg/mL) [intended to deliver 28 daily doses of 20 mcg] NDC 0548-2311-00 (Stock No. 2311). 16.2 Storage and Handling Store Teriparatide injection under refrigeration at 2° to 8°C (36° 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 if it has been frozen. Throw away the device 28 days after first use.

16.1 How Supplied Teriparatide injection is a clear and colorless solution, available as single-patient-use prefilled delivery device (pen) in the following package size: 560 mcg/2.24 mL (250 mcg/mL) [intended to deliver 28 daily doses of 20 mcg] NDC 0548-2311-00 (Stock No. 2311).