Bonsity Drug Information

Recommended Dosage

The recommended dosage is 20 mcg given subcutaneously once a day. Instruct patients to take supplemental calcium and vitamin D if daily dietary intake is inadequate.

Administration Instructions Administer

BONSITY as a subcutaneous injection into the thigh or abdominal region. BONSITY is not approved for intravenous or intramuscular use. BONSITY should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration (BONSITY 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 BONSITY should receive appropriate training and instruction on the proper use of the BONSITY delivery device from a qualified health professional.

Recommended Treatment Duration 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 .

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 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) . The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to teriparatide 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 group and 1% in the placebo group. The incidence of serious adverse events was 16% in the teriparatide group and 19% in the placebo group. Early discontinuation due to adverse events occurred in 7% in the teriparatide 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 N=691 Placebo N=691 Event Classification (%) (%) Body as a Whole Pain 21.3

Headache 7.5 7.4 Asthenia 8.7 6.8 Neck pain 3.0 2.7 Cardiovascular Hypertension

7.1

Angina pectoris 2.5 1.6 Syncope 2.6 1.4 Digestive System Nausea 8.5 6.7

Constipation 5.4

Tooth disorder 2.0 1.3 Musculoskeletal Arthralgia 10.1 8.4 Leg cramps 2.6 1.3

Nervous System Dizziness 8.0

Depression 4.1 2.7 Insomnia 4.3 3.6 Vertigo 3.8 2.7 Respiratory System Rhinitis

9.6

Skin and Appendages Rash 4.9 4.5 Sweating 2.2 1.7 Laboratory Findings Serum

Calcium - Teriparatide 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 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 whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men. Urinary Calcium - Teriparatide increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with teriparatide and placebo . Serum Uric Acid - Teriparatide 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 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. The duration of the trial was 18 months with 214 patients exposed to teriparatide 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 patients and 18% in active control patients, and included pneumonia (3% teriparatide, 1% active control). Early discontinuation because of adverse events occurred in 15% of teriparatide patients and 12% of active control patients, and included dizziness (2% teriparatide, 0% active control). Adverse events reported at a higher incidence in the teriparatide 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.

Postmarketing Experience Adverse Reactions from Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post-approval use of teriparatide. 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 . Hypercalcemia greater than 13 mg/dL has been reported with teriparatide use.

Adverse events reported since market introduction that were temporally related to teriparatide 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 Sporadic case reports have suggested that hypercalcemia may predispose patients to

digitalis toxicity. Teriparatide may transiently increase serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when BONSITY is used in patients receiving digoxin .

Pregnancy Risk Summary There are no available data on BONSITY use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider discontinuing BONSITY 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.

Pediatric Use The safety and effectiveness of teriparatide have not been established in pediatric patients. Pediatric patients are at higher baseline risk of osteosarcoma because of open epiphyses .

is contraindicated in patients with hypersensitivity to teriparatide or to any of its excipients. Hypersensitivity reactions have included angioedema and anaphylaxis . Patients with hypersensitivity to teriparatide or to any of its excipients

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 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 overdosage may include a delayed hypercalcemic effect, vomiting, dizziness, and headache. Overdose Management - There is no specific antidote for a teriparatide overdosage. Treatment of suspected overdosage should include discontinuation of BONSITY, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.