WARNINGS
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 (see BLACK BOX WARNING and PRECAUTIONS; Carcinogenesis).
The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO:
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Paget’s disease of bone. FORTEO should not be given to patients with Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone.
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Pediatric populations. FORTEO has not been studied in pediatric populations. FORTEO should not be used in pediatric patients or young adults with open epiphyses.
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Prior external beam or implant radiation therapy involving the skeleton. FORTEO should not be given to such patients.
Patients with bone metastases or a history of skeletal malignancies should be excluded from treatment with FORTEO.
Patients with metabolic bone diseases other than osteoporosis should be excluded from treatment with FORTEO.
FORTEO has not been studied in patients with pre–existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia.
PRECAUTIONS
General
The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended.
In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and placebo. However, FORTEO 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. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.
Hypotension
In short–term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed infrequently. 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.
Concomitant treatment with digitalis
In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO 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, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis.
Hepatic, renal, and cardiac
Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease.
Information for Patients
For safe and effective use of FORTEO, the physician should inform patients about the following:
General
Patients should read the Medication Guide and pen User Manual before starting therapy with FORTEO and re–read them each time the prescription is renewed.
Osteosarcomas in rats
Patients should be made aware that FORTEO caused osteosarcomas in rats and that the clinical relevance of these findings is unknown.
Orthostatic hypotension
FORTEO should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms occur. Patients should be instructed that if they feel lightheaded or have palpitations after the injection, they should sit or lie down until the symptoms resolve. If symptoms persist or worsen, patients should be instructed to consult a physician before continuing treatment (see PRECAUTIONS, General).
Hypercalcemia
Although symptomatic hypercalcemia was not observed in clinical trials, physicians should instruct patients to contact a health care provider if they develop persistent symptoms of hypercalcemia (ie, nausea, vomiting, constipation, lethargy, muscle weakness).
Use of the pen
Patients should be instructed on how to properly use the delivery device (refer to User Manual), properly dispose of needles, and be advised not to share their pens with other patients.
Other osteoporosis treatments
Patients should be informed regarding the roles of supplemental calcium and/or vitamin D, weight–bearing exercise, and modification of certain behavioral factors such as cigarette smoking and/or alcohol consumption.
Laboratory Tests
Serum calcium
FORTEO transiently increases serum calcium, with the maximal effect observed at approximately 4 to 6 hours post–dose. By 16 hours post–dose, serum calcium generally has returned to or near baseline. These effects should be kept in mind because serum calcium concentrations observed within 16 hours after a dose may reflect the pharmacologic effect of teriparatide. Persistent hypercalcemia was not observed in clinical trials with FORTEO. If persistent hypercalcemia is detected, treatment with FORTEO should be discontinued pending further evaluation of the cause of hypercalcemia.
Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with FORTEO (see WARNINGS).
Urinary calcium
FORTEO increases urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo (see CLINICAL PHARMACOLOGY, Human Pharmacodynamics).
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. Long–term evaluation of patients with severe renal insufficiency, patients undergoing acute or chronic dialysis, or patients who have functioning renal transplants has not been performed.
Serum uric acid
FORTEO increases serum uric acid concentrations. In clinical trials, 2.8% of FORTEO patients had serum uric acid concentrations above the upper limit of normal compared with 0.7% of placebo patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose–related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high–dose groups. Teriparatide also caused a dose–related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.
The second 2–year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20–mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed when immature 2–month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day for 6 months. Bone tumors were also observed when mature 6–month old rats were treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected when mature 6–month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.
The relevance of these rat findings to humans is uncertain.
Mutagenesis
Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.
Impairment of fertility
No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).
Pregnancy
Pregnancy Category C — In pregnant rats given subcutaneous teriparatide doses up to 1000 mcg/kg/day, there were no findings. In pregnant mice given subcutaneous doses of 225 or 1000 mcg/kg/day (≥60 times the human dose based on surface area, mcg/m2) from gestation Day 6 through 15, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib).
Developmental effects in a perinatal/postnatal study in pregnant rats given subcutaneous doses of teriparatide from gestation Day 6 through postpartum Day 20 included mild growth retardation in female offspring at doses ≥225 mcg/kg/day (≥120 times the human dose based on surface area, mcg/m2), and in male offspring at 1000 mcg/kg/day (540 times the human dose based on surface area, mcg/m2). There was also reduced motor activity in both male and female offspring at 1000 mcg/kg/day. There were no developmental or reproductive effects in mice or rats at a dose of 30 mcg/kg (8 or 16 times the human dose based on surface area, mcg/m2). The effect of teriparatide treatment on human fetal development has not been studied. FORTEO is not indicated for use in pregnancy.
Nursing Mothers
Because FORTEO is indicated for the treatment of osteoporosis in postmenopausal women, it should not be administered to women who are nursing their children. There have been no clinical studies to determine if teriparatide is secreted into breast milk.
Pediatric Use
The safety and efficacy of FORTEO have not been established in pediatric populations. FORTEO is not indicated for use in pediatric patients (see WARNINGS).
Geriatric Use
Of the patients receiving FORTEO in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving FORTEO in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. No significant differences in bone response or adverse reactions were seen in geriatric patients receiving FORTEO as compared with younger patients. Nonetheless, as with many medications, elderly patients may have greater sensitivity to the adverse effects of FORTEO.
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