FORTEO

Teriparatide is a recombinant parathyroid hormone (PTH) analog and a potent osteoanabolic agent.

It is made up of the first amino(N)-terminal 34 amino acids of the human PTH.

First approved in the United States in November and in Europe in April 2003, 3 teriparatide makes the first approved drug in a new category of osteoporosis therapy called anabolic therapy.

Teriparatide is used in the treatment of osteoporosis in men and women. 4, 5.

Teriparatide 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 reduces the risk of vertebral and nonvertebral fractures. 4, 5, 7, 8 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. 4, 5, 7, 8 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. 4, 5, 7,

Teriparatide is a

PTH analog that works to stimulate bone formation in both men and women.

It increases skeletal mass, increases markers of bone formation such as bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP), and increases bone strength.

Like endogenous

PTH, teriparatide affects calcium and phosphate homeostasis.

It causes a transient increase in serum calcium levels and increases urinary calcium excretion.

In clinical trials, it also produced transient phosphaturia and mild transient reductions in serum phosphorus concentration.

Parathyroid hormone (PTH) is an endogenous hormone that regulates calcium and phosphate metabolism in bone and kidney.

It regulates bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption.

It mediates its physiological actions by binding to the PTH receptors.

• such as in certain disease states like hyperparathyroidism.

• can cause increased osteoclast activity and accelerated bone resorption.

Interestingly, the effects of PTH depend on the dose and pattern of exposure of PTH to the bone.

Continuous exposure to

PTH promotes bone resorption, whereas intermittent exposure to low-dose PTH can induce bone formation more favourably than bone resorption.

Similarly, teriparatide's skeletal effects depend upon the systemic exposure pattern.

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.

Teriparatide mediates its osteoanabolic actions by binding to the N-terminal moiety to PTH type 1 receptors (PTH type 1R), which are G-protein coupled receptors expressed on various cells, including osteoblasts, osteocytes, and renal tubular cells.

Binding of teriparatide to

PTH receptors on osteoblasts activates the downstream PKA.

• and PKC-dependent signaling pathways that promotes anabolic effects on bone. 1, 2 For example, teriparatide increases expression of pro-osteoclastogenic cytokines like receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor.

It also upregulates transcriptional expression of pro-osteoblastogenic growth factors like insulin-like growth factor 1 (IGF1) and fibroblast growth factor 2 (FGF2).

Teriparatide also downregulates the synthesis of sclerostin, which is a negative regulator of bone formation.

It also promotes the differentiation of osteoblasts.

Target Actions Organism U Parathyroid hormone modulator Humans U Parathyroid hormone/parathyroid hormone-related peptide receptor ligand Humans.

The absolute bioavailability is approximately 95%.

The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20 mcg dose and declines to non-quantifiable concentrations within three hours.

The volume of distribution following intravenous injection is approximately 0.12 L/kg. Teriparatide is not expected to accumulate in bone or other tissues.

No metabolism studies have been performed with teriparatide.

Peripheral metabolism of

PTH is believed to occur by non-specific enzymatic mechanisms in the liver.

No excretion studies have been performed with teriparatide.

It is believed to be excreted via the kidneys.

The half-life of teriparatide in serum was approximately one hour following subcutaneous administration.

Systemic clearance of teriparatide is approximately 62 L/hour in women and 94 L/hour in men.

It exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance.

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The subcutaneous and intravenous lethal dose (LD) in rats are 1000 µg/m and 300 µg/m 3, respectively.

Few post-marketing reports illustrate cases of medication errors where patients accidentally received up to a single 800 mcg dose of teriparatide, which is 40 times the recommended dose.

Patients experienced nausea, weakness or lethargy, and hypotension.

No deaths have been reported from teriparatide overdose.

Additional signs, symptoms, and complications of overdosage may include a delayed hypercalcemic effect, vomiting, dizziness, and headache.

There is no specific antidote for a teriparatide overdosage.

Treatment of suspected overdosage should include discontinuation of teriparatide, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

Teriparatide injection 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.

Recommended dosage is 20 mcg subcutaneously once a day Consider supplemental calcium and Vitamin D based on individual patient needs Administer as a subcutaneous injection into the thigh or abdominal region Administer initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur 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 2.1 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. 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.

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 delivery device from a qualified health professional. 2.3 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.

Teriparatide injection is a colorless solution, available as single-patient-use prefilled pens in the following package size: 560 mcg/2.24 mL (250 mcg/mL) NDC 47781-652-89. 16.2 Storage and Handling The teriparatide injection delivery device should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) at all times.

Recap the delivery device 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.

The teriparatide injection delivery device should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) at all times.

Recap the delivery device 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.

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.

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.

In animal reproduction studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses equivalent to 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 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.

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.

Of the patients who received teriparatide 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 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 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 have been observed between patients 65 years of age and older and younger adult patients.