BONSITY (teriparatide injection)

BONSITY (teriparatide injection)

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BONSITY (teriparatide injection)

BONSITY (teriparatide injection) is a recombinant human 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 C181H291N55O51S2 and the molecular weight is 4117.8 daltons.

Teriparatide is manufactured using a strain of Pseudomonas fluorescens modified by recombinant DNA technology. BONSITY 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 pen is filled to deliver 2.48 mL. Each mL contains 250 mcg teriparatide (as a free base), 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection. The drug product is a pH 4.0 solution.

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

Indications and usage

BONSITY is a parathyroid hormone analog (PTH 1-34) indicated for:

Treatment of postmenopausal women with osteoporosis at high risk for fracture: BONSITY is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, BONSITY reduces the risk of vertebral and nonvertebral fractures

Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture: BONSITY is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy

Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture: BONSITY is indicated 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, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy

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.

Dosage and administration

Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture: The recommended dose is 20 mcg subcutaneously once a day.

Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture: The recommended dose is 20 mcg subcutaneously once a day.

Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture: The recommended dose is 20 mcg subcutaneously once a day.

Administration

  • BONSITY should be administered as a subcutaneous injection into the thigh or abdominal wall. There are no data available on the safety or efficacy of intravenous or intramuscular injection of BONSITY.
  • 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, whenever solution and container permit. BONSITY is a clear and colorless liquid. Do not use if solid particles appear or if the solution is cloudy or colored.
  • Patients and caregivers who administer BONSITY should receive appropriate training and instruction on the proper use of the BONSITY delivery device from a qualified health professiona

Treatment Duration

The safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patient’s lifetime is not recommended.

Contraindications

BONSITY is contraindicated in patients with:

  • Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis

Warnings and precautions

Osteosarcoma: In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. BONSITY should not be prescribed for patients at increased baseline risk of osteosarcoma.

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These include:

  • Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone.
  • Pediatric and young adult patients with open epiphyses.
  • Prior external beam or implant radiation therapy involving the skeleton.

Bone Metastases and Skeletal Malignancies: Patients with bone metastases or a history of skeletal malignancies should not be treated with BONSITY.

Metabolic Bone Diseases: Patients with metabolic bone diseases other than osteoporosis should not be treated with BONSITY.

Hypercalcemia and Hypercalcemic Disorders: Teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with teriparatide because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with BONSITY.

Urolithiasis or Pre-existing Hypercalciuria: In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo. However, teriparatide has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. BONSITY should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

Orthostatic Hypotension: BONSITY 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 with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. Typically, an event began within 4 hours of dosing and spontaneously resolved 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.

Drug Interactions: Hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium, patients receiving digoxin should use BONSITY with caution

Adverse reactions

  • 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

Drug interactions

Digoxin: A single teriparatide 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). However, because teriparatide may transiently increase serum calcium, BONSITY should be used with caution in patients taking digoxin

Hydrochlorothiazide: The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg. The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied

Furosemide: Coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg in healthy people and patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min) resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important

Use in specific populations

Pregnancy: 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.

Lactation: It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breast fed infant. Because of the potential for osteosarcoma shown with teriparatide in animal studies, advise patients that breastfeeding is not recommended during treatment with BONSITY

Pediatric Use: The safety and efficacy of teriparatide have not been established in any pediatric population. BONSITY should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, BONSITY is not indicated for use in pediatric or young adult patients with open epiphyses

Hepatic Impairment: No studies have been performed in patients with hepatic impairment

Renal Impairment: In 5 patients with severe renal impairment (CrCl <30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased

Overdosage

Incidents of overdose in humans have not been reported in clinical trials. Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur.

In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) of the teriparatide delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated with overdose have been reported.

Overdose Management

There is no specific antidote for teriparatide. Treatment of suspected overdose should include discontinuation of BONSITY, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

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