FORTEO (teriparatide injection)

FORTEO (teriparatide injection)

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FORTEO (teriparatide injection)

FORTEO (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 molecular weight is 4117.8 daltons.

Teriparatide is manufactured using a strain of Escherichia coli modified by recombinant DNA technology.

FORTEO 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 2.7 mL to deliver 2.4 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.

Indications and usage

FORTEO is a 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
  • 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
  • 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

Dosage and administration

  • 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 FORTEO 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

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.

Pharmacokinetics

Absorption: Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80- mcg doses (1-, 2-, and 4- times the recommended dosage, respectively). The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.

Distribution: Volume of distribution following intravenous injection is approximately 0.12 L/kg..

Elimination: Systemic clearance of teriparatide (approximately 62 L/hour in women and 94 L/hour in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. The half-life of teriparatide in serum was approximately 1 hour when administered by subcutaneous injection.

No metabolism or excretion studies have been performed with teriparatide. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.

Contraindications

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

Adverse reactions

Most common adverse reactions (>10%) include: arthralgia, pain, and nausea

Warnings and precautions

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 FORTEO 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 FORTEO use.

Avoid FORTEO use in patients with (these patients are at increased baseline risk of osteosarcoma):

  • Open epiphyses (pediatric and young adult patients) (FORTEO is not approved in pediatric patients)
  • 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.

Hypercalcemia: FORTEO has not been studied in patients with pre-existing hypercalcemia. FORTEO may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia. Avoid FORTEO 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 FORTEO. Risk factors for development of calciphylaxis include underlying autoimmune disease, kidney failure, and concomitant warfarin or systemic corticosteroid use. Discontinue FORTEO in patients who develop calciphylaxis or worsening of previously stable cutaneous calcification.

Risk of Urolithiasis: In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and patients treated with placebo. However, FORTEO has not been studied in patients with active urolithiasis. If FORTEO-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.

Orthostatic Hypotension: FORTEO 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 FORTEO 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.

Risk of Digoxin Toxicity: Hypercalcemia may predispose patients to digitalis toxicity because FORTEO transiently increases serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when FORTEO is used in patients receiving digoxin.

Drug interactions

dic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. FORTEO may transiently increase serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when FORTEO is used in patients receiving digoxin

Use in specific populations

Pregnancy: There are no available data on FORTEO use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider discontinuing FORTEO 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 breastfed infant. Avoid FORTEO use in women who are breastfeeding.

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

Geriatric Use: Of the patients who received FORTEO 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 FORTEO 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 FORTEO 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 FORTEO have been observed between patients 65 years of age and older and younger adult patients.

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

Renal Impairment: In 5 patients with severe renal impairment (CrCl<30 mL/minute), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. It is unknown whether FORTEO alters the underlying metabolic bone disease seen in chronic renal impairment.

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 FORTEO 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 FORTEO overdosage may include a delayed hypercalcemic effect, vomiting, dizziness, and headache.

Overdose Management

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

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