HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
` These highlights do not include all the information needed to use
` FORTEO safely and effectively. See full prescribing information
`
`
`
` for FORTEO.
`
`
`
` FORTEO (teriparatide injection), for subcutaneous use
` Initial U.S. Approval: 1987
`
`
`-----------------------------------------------
`
`
`
`
` ---------------------------- 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 (1)
`
`
`
`
`
` 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 (1)
`
`
`
`
`
` 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 (1)
`
` ------------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
` •
`
`
`
` Recommended dosage is 20 mcg subcutaneously once a day
`
` (2.1)
`Consider supplemental calcium and Vitamin D based on
`
`
`
` individual patient needs (2.1)
` Administer as a subcutaneous injection into the thigh or
`
`
` abdominal region (2.2)
` Administer initially under circumstances in which the patient can
`
`
`
` sit or lie down if symptoms of orthostatic hypotension occur (2.2)
` 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 (2.3)
`
`
`
` ----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`
`
`
` Injection: 560 mcg/2.24 mL (250 mcg/mL) in a single-patient-use
` prefilled delivery device (pen) intended to deliver 28 daily doses of
`
`
` 20 mcg (3)
`
` ------------------------------- CONTRAINDICATIONS ------------------------------
`
`
`
`
`
`
`
`
`
`
` •
`
`
`
` •
`
`
`
` •
`
`
`
` •
`
`
`
` •
`
`
`
` •
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1
`Recommended Dosage
`
`
`2.2
`Administration Instructions
`
`
`
`2.3
`Recommended Treatment Duration
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Osteosarcoma
`5.1
`
`
`
`
`5.2
`Hypercalcemia and Cutaneous Calcification
`
`
`5.3
`Risk of Urolithiasis
`
`
`5.4
`Orthostatic Hypotension
`
`
`5.5
`Risk of Digoxin Toxicity
`
`
`6 ADVERSE REACTIONS
`
`
`
`Clinical Trials Experience
`6.1
`
`
`6.2
`Immunogenicity
`
`
`6.3
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1
`Digoxin
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`
`8.6
`Hepatic Impairment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`Patients with hypersensitivity to teriparatide or to any of its
`
`
`
`
`excipients (4)
`
`
`------------------------ WARNINGS AND PRECAUTIONS -----------------------
`
`
`
`
`
`•
`Osteosarcoma: Avoid use in patients with increased risk of
`
`
`
`
`
`osteosarcoma including patients with open epiphyses, metabolic
`
`
`
`bone diseases including Paget’s disease, bone metastases or
`
`
`
`history of skeletal malignancies, prior external beam or implant
`
`
`
`
`
`radiation therapy involving the skeleton, and hereditary disorders
`
`
`
`
`
`predisposing to osteosarcoma. (5.1)
`
`
`Hypercalcemia and Cutaneous Calcification: Avoid in patients
`
`
`known to have an underlying hypercalcemic disorder. Discontinue
`
`
`in patients developing worsening of previously stable cutaneous
`
`
`
`calcification. (5.2)
`
`
`Risk of Urolithiasis: Consider the risk/benefit in patients with
`
`
`active or recent urolithiasis because of risk of exacerbation (5.3)
`
`
`
`Orthostatic Hypotension: Transient orthostatic hypotension may
`
`
`
`
`occur with initial doses of FORTEO (5.4)
`
`
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`
`
`
`
`Most common adverse reactions (>10%) include: arthralgia, pain, and
`
`
`
`
`nausea (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
`
`
`and Company at 1-800-545-5979 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch
`
`------------------------------- DRUG INTERACTIONS ------------------------------
`
`
`
`
`
`Digoxin: Transient hypercalcemia may predispose patients to digitalis
`
`
`
`toxicity (5.5, 7.1)
`
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`
`
`
`•
`Pregnancy: Consider discontinuing when pregnancy is recognized
`
`
`(8.1)
`
`Lactation: Breastfeeding is not recommended (8.2)
`
`
`Pediatric Use: Safety and effectiveness not established. Avoid
`
`
`
`use due to increased baseline risk of osteosarcoma (5.1, 8.4)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`Revised: 7/2024
`
`
`
`
`
`
`
`
`
`Renal Impairment
`8.7
`
`
`
` 10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
` 12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
`14.2 Treatment to Increase Bone Mass in Men with Primary or
`
`
`
`Hypogonadal Osteoporosis
`
`14.3 Treatment of Men and Women with Glucocorticoid-
`
`Induced Osteoporosis
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`
`

`

`
`
`
`
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`
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`
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`
`
`
`
`
`
`
`
`
` 2
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` INDICATIONS AND USAGE
` 1
` FORTEO 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, FORTEO reduces the risk of vertebral and
`
` nonvertebral fractures.
` • 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.
`
` • 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.
`
`
` 2
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1
`Recommended Dosage
`
`
`
`
`
` The recommended dosage is 20 mcg per dose 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 FORTEO as a subcutaneous injection into the thigh or abdominal region. FORTEO is not approved for
`
` intravenous or intramuscular use.
`
`
`
` • 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 (5.4)].
`
` • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration
`
`
`
`
`
`
` (FORTEO 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 FORTEO should receive appropriate training and instruction on the proper
`
`
`
`
`
` use of the FORTEO prefilled delivery device (pen) from a qualified health professional.
`
` • Discard the delivery device 28 days after first use.
`
`
` 2.3
` Recommended Treatment Duration
`
`
`
`
`
`
` 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 [see Warnings and Precautions (5.1)].
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
` 3
` Injection: 560 mcg/2.24 mL (250 mcg/mL) clear, colorless solution in a single-patient-use prefilled delivery device (pen)
`
`
`
`
` intended to deliver 28 daily doses of 20 mcg.
`
`
`
`
`
`
` 4
` CONTRAINDICATIONS
`
`
`
`
`
`
`
` FORTEO is contraindicated in patients with hypersensitivity to teriparatide or to any of its excipients. Hypersensitivity
`
` reactions have included angioedema and anaphylaxis [see Adverse Reactions (6.3)].
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 5
` 5.1
`
`
` 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 [see Dosage and Administration (2.3), Adverse
` Reactions (6.3), and Nonclinical Toxicology (13.1)].
`
`
`
`
` 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) [see Use in
`
`
` Specific Populations (8.4)].
`
` • 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
` 3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Hereditary disorders predisposing to osteosarcoma.
`
` Hypercalcemia and Cutaneous Calcification
` 5.2
`
`
` 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 [see Adverse Reactions (6.1, 6.3)]. 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 post-
` marketing setting in patients taking FORTEO. Risk factors for development of calciphylaxis include underlying auto-
`
`
` immune 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
` 5.3
`
`
`
`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
` 5.4
`
`
`
` 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
` 5.5
`
`
` 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`
`
` ADVERSE REACTIONS
` 6
` 6.1
` 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.
`
`
`
`
`
`
`
` Men with Primary or Hypogonadal Osteoporosis and Postmenopausal Women with Osteoporosis
`
` 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) [see Clinical Studies (14.1, 14.2)]. 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 the FORTEO group and 19% in the placebo group. Early discontinuation due to adverse
`
`
`
`
`
`
`
`
` events occurred in 7% in the FORTEO group and 6% in the placebo group.
`
`
`
`
`
`
`
`
` Table 1 lists adverse events from these two trials that occurred in ≥2% of FORTEO-treated and more frequently than
`
`
`
` placebo-treated patients.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

` Table 1: Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients and in
`
`
`
`
`
`
`
` More FORTEO-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in
` Women and Men Adverse Events are Shown Without Attribution of Causality
`
`
`
`
`
` FORTEO
`
`
` N=691
`
` (%)
`
`
` 21.3
`
` 7.5
`
` 8.7
`
` 3.0
`
`
` 7.1
`
` 2.5
`
` 2.6
`
`
` 8.5
`
` 5.4
`
` 5.1
`
` 5.2
`
` 3.0
`
` 2.3
`
` 2.0
`
`
` 10.1
`
` 2.6
`
`
` 8.0
`
` 4.1
`
` 4.3
`
` 3.8
`
`
` 9.6
`
` 6.4
`
` 5.5
`
` 3.6
`
` 3.9
`
`
` 4.9
`
` 2.2
`
`
` Event Classification
`
` Body as a Whole
`
`
`
` Pain
`
`
` Headache
`
` Asthenia
`
`
`
` Neck pain
`
` Cardiovascular
`
` Hypertension
`
`
` Angina pectoris
`
` Syncope
`
`
` Digestive System
`
` Nausea
`
`
` Constipation
`
` Diarrhea
`
`
` Dyspepsia
`
` Vomiting
`
`
` Gastrointestinal disorder
`
` Tooth disorder
`
`
` Musculoskeletal
`
` Arthralgia
`
`
`
` Leg cramps
`
` Nervous System
`
` Dizziness
`
`
` Depression
`
` Insomnia
`
`
` Vertigo
`
`
` Respiratory System
`
` Rhinitis
`
`
` Cough increased
`
` Pharyngitis
`
`
` Dyspnea
`
`
`
` Pneumonia
`
` Skin and Appendages
`
` Rash
`
`
` Sweating
`
`
`
` 4
`
`
`
`
` Placebo
`
` N=691
`
` (%)
`
`
` 20.5
`
` 7.4
`
` 6.8
`
` 2.7
`
`
` 6.8
`
` 1.6
`
` 1.4
`
`
` 6.7
`
` 4.5
`
` 4.6
`
` 4.1
`
` 2.3
`
` 2.0
`
` 1.3
`
`
` 8.4
`
` 1.3
`
`
` 5.4
`
` 2.7
`
` 3.6
`
` 2.7
`
`
` 8.8
`
` 5.5
`
` 4.8
`
` 2.6
`
` 3.3
`
`
` 4.5
`
` 1.7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 11% of women and 6% of men treated with FORTEO compared to 2% of women and 0% of the men
`
`
`
`
`
`
`
`
`
`treated with placebo. The percentage 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)].
`
`
`
`
`
`

`

`
`
` 5
`
`
`
`
`
` Serum Uric Acid — FORTEO increased serum uric acid concentrations. In clinical trials, 3% of FORTEO-treated patients
`
`
`
`
`
`
` had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo-treated 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.
`
`
`
`
` 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 [see Clinical Studies (14.3)]. The
`
`
`
`
`
`
`
`
`
`
` duration of the trial was 18 months with 214 patients exposed to FORTEO and 214 patients exposed to an oral daily
` bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per
`
`
`
`
`
`
`
` day.
`
`
`
`
`
`
`
`
` There was no increase in mortality in the FORTEO group compared to 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.
`
`
`
`
`
`
`
` Immunogenicity
` 6.2
`
`
` As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the
`
`
` sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody)
`
` positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of
` sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of
`
`
`
`
`
`
` antibodies in the studies described below with the incidence of antibodies in other studies or to other teriparatide products
` may be misleading.
`
`
`In the clinical trial of postmenopausal women with osteoporosis [see Clinical Studies (14.1)], antibodies that cross reacted
`
`
`
`
`with teriparatide were detected in 3% of women (15/541) who received FORTEO. Generally, antibodies were first
`
`
`detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of
`
`
`hypersensitivity reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or
`
`
`
`on bone mineral density (BMD) response.
`
`
`Postmarketing Experience
`6.3
`
`
`Adverse Reactions from Postmarketing Spontaneous Reports
`
`
`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.
`
`
`• Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period [see Warnings and
`
`
`
`Precautions (5.2)].
`
`• Hypercalcemia greater than 13 mg/dL has been reported with FORTEO use.
`
`
`
`
`
`Adverse events reported since market introduction that were temporally 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
`
`
`
`
`
`
`
`
`
`
`

`

`
`
` 6
`
`
`Adverse Reactions from Observational Studies to Assess Incidence of Osteosarcoma
`
`
`Two osteosarcoma surveillance safety studies (U.S. claims-based database studies) were designed to obtain data on the
`
`incidence rate of osteosarcoma among FORTEO-treated patients. In these two studies, three and zero osteosarcoma
`
`cases were identified among 379,283 and 153,316 FORTEO users, respectively. The study results suggest a similar risk
`
`
`
`
`for osteosarcoma between FORTEO users and their comparators. However, the interpretation of the study results calls for
`
`caution owing to the limitations of the data sources which do not allow for complete measurement and control for
`
`
`confounders.
`
`
`DRUG INTERACTIONS
`7
`
`
`7.1
`Digoxin
`
`
`Sporadic 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 [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`8.1
`Pregnancy
`
`
`Risk Summary
`
`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.
`
`
`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/m2), and produced mild growth retardation and reduced motor activity in rat offspring at subcutaneous
`
`
`doses equivalent to more than 120 times the human dose (see Data).
`
`
`
`
`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.
`
`
`Data
`
`Animal Data
`
`In animal reproduction studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses
`
`
`
`
`
`equivalent to 8 to 267 times the human dose (based on body surface area, mcg/m2). 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 16 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.
`
`
`Lactation
`8.2
`
`
`Risk Summary
`
`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
`8.4
`
`
`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 [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`

`

`
`
`
`
` 7
`
`
`
`
`
`
`
` 8.5
` 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
` 8.6
`
`
` No studies have been performed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
`
`Renal Impairment
`
`
` 8.7
`
`
` 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 [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
` 10
` 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.
`
` DESCRIPTION
` 11
`
`
`
`
`
`
`
`
` 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. Its amino acid
`
`
`
`
`
`
`sequence is shown below:
`
`
`
`
`
`
`
`
`
`
`
`
`30
`
`
`
`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 volume to
`
`
`
`
`
`
`
`
`allow delivery of 2.24 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.
`
`
`
`

`

`
`
` 8
`
`
`Each prefilled delivery device (pen) delivers 20 mcg of teriparatide per dose for up to 28 days. Each device contains
`
`
`
`
`
`
`
`additional volume to allow troubleshooting of the device 2 times.
`
`
`
`CLINICAL PHARMACOLOGY
`12
`
`
`12.1 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.
`
`
`12.2 Pharmacodynamics
`
`
`Pharmacodynamics in Men with Primary or Hypogonadal Osteoporosis 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 was administered once daily, the serum calcium
`
`
`
`
`
`
`concentration increased 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 began to decline approximately
`
`
`
`
`
`
`6 hours after dosing and returned 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 (20 mcg subcutaneous once daily) was 9.68 mg/dL at 12 months. The peak serum
`
`
`
`
`
`
`
`
`calcium remained below 11 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
`
`
`
`
`(ULN) (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 ULN on consecutive 4- to 6-hour post-dose measurements was 3% 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 9.44 mg/dL at 12 months. The peak serum calcium remained below 11 mg/dL in 98% of men at
`
`
`
`
`
`
`e