Generic Name: teriparatide
Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
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. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma finding to humans, prescribe Forteo® only for patients for whom the potential benefits are considered to outweigh the potential risk. Forteo should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton) [see Warnings and Precautions (5.1), Adverse Reactions (6.2), and Nonclinical Toxicology (13.1)].
Indications and Usage for Forteo
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture
Forteo 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, Forteo reduces the risk of vertebral and nonvertebral fractures [see Clinical Studies (14.1)].
Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture
Forteo 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 [see Clinical Studies (14.2)].
Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture
Forteo 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 [see Clinical Studies (14.3)].
Forteo 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
- Forteo 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 Forteo.
- Forteo should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur [see Warnings and Precautions (5.7)].
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Forteo 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 Forteo should receive appropriate training and instruction on the proper use of the Forteo delivery device from a qualified health professional [see Patient Counseling Information (17.5)].
Treatment Duration
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 during a patient's lifetime is not recommended.
Dosage Forms and Strengths
Multi-dose prefilled delivery device (pen) for subcutaneous injection containing 28 daily doses of 20 mcg.
Contraindications
Do not use Forteo in patients with:
- Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis [see Adverse Reactions (6.2)].
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 [see Boxed Warning and Nonclinical Toxicology (13.1)]. Forteo should not be prescribed for patients at increased baseline risk of osteosarcoma.
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.
Patients should be encouraged to enroll in the voluntary Forteo Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken Forteo. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.Forteoregistry.rti.org
Treatment Duration
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 during a patients' lifetime is not recommended.
Bone Metastases and Skeletal Malignancies
Patients with bone metastases or a history of skeletal malignancies should not be treated with Forteo.
Metabolic Bone Diseases
Patients with metabolic bone diseases other than osteoporosis should not be treated with Forteo.
Hypercalcemia and Hypercalcemic Disorders
Forteo has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with Forteo because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with Forteo.
Urolithiasis or Pre-existing Hypercalciuria
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.
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 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 Forteo transiently increases serum calcium, patients receiving digoxin should use Forteo with caution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Adverse Reactions
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.
Treatment of Osteoporosis in Men and Postmenopausal Women
The safety of Forteo 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 Forteo 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 Forteo group and 1% in the placebo group. The incidence of serious adverse events was 16% in Forteo patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 7% of Forteo patients and 6% of placebo patients.
Table 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in ≥2% of Forteo-treated and more frequently than placebo-treated patients.
| Forteo N=691 | Placebo N=691 | |
| Event Classification | (%) | (%) |
| Body as a Whole | ||
| Pain | 21.3 | 20.5 |
| Headache | 7.5 | 7.4 |
| Asthenia | 8.7 | 6.8 |
| Neck pain | 3.0 | 2.7 |
| Cardiovascular | ||
| Hypertension | 7.1 | 6.8 |
| Angina pectoris | 2.5 | 1.6 |
| Syncope | 2.6 | 1.4 |
| Digestive System | ||
| Nausea | 8.5 | 6.7 |
| Constipation | 5.4 | 4.5 |
| Diarrhea | 5.1 | 4.6 |
| Dyspepsia | 5.2 | 4.1 |
| Vomiting | 3.0 | 2.3 |
| Gastrointestinal disorder | 2.3 | 2.0 |
| Tooth disorder | 2.0 | 1.3 |
| Musculoskeletal | ||
| Arthralgia | 10.1 | 8.4 |
| Leg cramps | 2.6 | 1.3 |
| Nervous System | ||
| Dizziness | 8.0 | 5.4 |
| Depression | 4.1 | 2.7 |
| Insomnia | 4.3 | 3.6 |
| Vertigo | 3.8 | 2.7 |
| Respiratory System | ||
| Rhinitis | 9.6 | 8.8 |
| Cough increased | 6.4 | 5.5 |
| Pharyngitis | 5.5 | 4.8 |
| Dyspnea | 3.6 | 2.6 |
| Pneumonia | 3.9 | 3.3 |
| Skin and Appendages | ||
| Rash | 4.9 | 4.5 |
| Sweating | 2.2 | 1.7 |
Immunogenicity — In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) receiving Forteo. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.
Laboratory Findings
Serum Calcium — Forteo 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 Forteo administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with Forteo. The number of patients treated with Forteo whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.
Urinary Calcium — Forteo increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with Forteo and placebo [see Clinical Pharmacology (12.2)].
Serum Uric Acid — Forteo increased serum uric acid concentrations. In clinical trials, 3% of Forteo patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo 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.
Studies in Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of Forteo 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 ≥ 5mg per day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to Forteo and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 4% in the Forteo group and 6% in the active control group. The incidence of serious adverse events was 21% in Forteo patients and 18% in active control patients, and included pneumonia (3% Forteo, 1% active control). Early discontinuation because of adverse events occurred in 15% of Forteo patients and 12% of active control patients, and included dizziness (2% Forteo, 0% active control).
Adverse events reported at a higher incidence in the Forteo group and with at least a 2% difference in Forteo-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
The following adverse reactions have been identified during postapproval use of Forteo. 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.
- Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period. The causality to Forteo use is unclear. Long term osteosarcoma surveillance studies are ongoing [see Warnings and Precautions (5.1)]
- Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with Forteo use.
Adverse events reported since market introduction that were temporally (but not necessarily causally) related to Forteo 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
Drug Interactions
Digoxin
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, because Forteo may transiently increase serum calcium, Forteo should be used with caution in patients taking digoxin [see Warnings and Precaution (5.8) and Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C — There are no adequate and well-controlled studies of Forteo in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. Forteo should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At 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 subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.
In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 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.
Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).
Nursing Mothers
It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of Forteo have not been established in any pediatric population. Forteo should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, Forteo is not indicated for use in pediatric or young adult patients with open epiphyses [see Warnings and Precautions (5.1)].
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 overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
No studies have been performed in patients with hepatic impairment. [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
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 Forteo 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 Forteo, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.
Forteo Description
Forteo (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1-34), and is also called rhPTH (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.
Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:
Teriparatide (rDNA origin) 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 disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.
Forteo - Clinical Pharmacology
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.
Pharmacodynamics
Pharmacodynamics in Men and Postmenopausal Women with Osteoporosis
Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).
Serum Calcium Concentrations — When teriparatide 20 mcg is administered once daily, the serum calcium concentration increases transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose.
In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 6 hours after dosing with Forteo (teriparatide 20 mcg) was 2.42 mmol/L (9.68 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in >99% of women at each visit. Sustained hypercalcemia was not observed.
In this study, 11.1% of women treated with Forteo had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with 1.5% of women treated with placebo. The percentage of women treated with Forteo whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour post-dose measurements was 3.0% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or Forteo doses were reduced. The timing of these dose reductions was at the discretion of the investigator. Forteo dose adjustments were made at varying intervals after the first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive increases in serum calcium.
In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with Forteo was 2.35 mmol/L (9.44 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in 98% of men at each visit. Sustained hypercalcemia was not observed.
In this study, 6.0% of men treated with Forteo daily had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with none of the men treated with placebo. The percentage of men treated with Forteo whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Although calcium supplements and/or Forteo doses could have been reduced in these men, only calcium supplementation was reduced [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum calcium >12 hours after Forteo injection was increased by 0.09 to 0.14 mmol/L (0.36 to 0.56 mg/dL), after 1 to 6 months of Forteo treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >2.76 mmol/L (11.0 mg/dL), and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >2.76 mmol/L (11.0 mg/dL). The highest serum calcium reported was 3.12 mmol/L (12.5 mg/dL). None of the women had symptoms of hypercalcemia. There were no placebo controls in this study.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of Forteo on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily Forteo increased urinary calcium excretion. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.3 mmol/day (12 mg/day) higher, respectively, than in women treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the women treated with Forteo or placebo.
In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily Forteo had inconsistent effects on urinary calcium excretion. The median urinary excretion of calcium was 5.6 mmol/day (220 mg/day) at 1 month and 5.3 mmol/day (210 mg/day) at 6 months. These levels were 0.5 mmol/day (20 mg/day) higher and 0.2 mmol/day (8.0 mg/day) lower, respectively, than in men treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the men treated with Forteo or placebo.
Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia (<0.74 mmol/L or 2.4 mg/dL) was not observed in clinical trials with Forteo.
In clinical trials of daily Forteo, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of Forteo on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Effects on Markers of Bone Turnover — Daily administration of Forteo to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of Forteo on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
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. The rates of absorption and elimination are rapid. 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 — Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous injection, is approximately 0.12 L/kg. Intersubject variability in systemic clearance and volume of distribution is 25% to 50%. The half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for absorption from the injection site.
Metabolism and Excretion — No metabolism or excretion studies have been performed with teriparatide. However, the mechanisms of metabolism and elimination of PTH(1-34) and intact PTH have been extensively described in published literature. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.
Pediatric Patients — Pharmacokinetic data in pediatric patients are not available [see Warnings and Precautions (5.1)].
Geriatric Patients — No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years).
Gender — Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dose for both genders is 20 mcg/day.
Race — The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been determined.
Renal Impairment — No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. 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. No studies have been performed in patients undergoing dialysis for chronic renal failure [see Use in Specific Populations (8.7)].
Hepatic Impairment — No studies have been performed in patients with hepatic impairment. Non-specific proteolytic enzymes in the liver (possibly Kupffer cells) cleave PTH(1-34) and PTH(1-84) into fragments that are cleared from the circulation mainly by the kidney [see Use in Specific Populations (8.6)].
Drug Interactions
Digoxin — 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 may transiently increase serum calcium, Forteo should be used with caution in patients taking digoxin [see Drug Interactions (7.1)].
Hydrochlorothiazide — In a study of 20 healthy people, the coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg. The 24-hour urine excretion of calcium was reduced by a clinically unimportant amount (15%). The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied [see Drug Interactions (7.2)].
Furosemide — In a study of 9 healthy people and 17 patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min), coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg 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 [see Drug Interactions (7.3)].
Nonclinical Toxicology
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 animal 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).
Animal Toxicology
In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose based on surface area, mcg/m2).
In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic
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