CLASSES
Parathyroid Hormone Analogs and Modifiers
DESCRIPTION
Recombinant human parathyroid hormone
Used for the treatment of osteoporosis in patients with high risk of fracture
Boxed warning regarding the risk of osteosarcoma; not recommended for use in patients at risk for osteosarcoma
COMMON BRAND NAMES
FORTEO
HOW SUPPLIED
Forteo/Teriparatide Subcutaneous Inj Sol: 1mL, 250mcg
DOSAGE & INDICATIONS
For the treatment of osteoporosis.
For osteoporosis in postmenopausal women or in men with primary or hypogonadal osteoporosis at high risk for fracture.
Subcutaneous dosage
Adults
20 mcg subcutaneously once daily. Patients at high risk of fracture are defined as those with history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Supplement calcium and vitamin D if dietary intake is inadequate. Follow teriparatide treatment with a bisphosphonate or denosumab to prevent decline in bone density and loss of efficacy against fracture. Use of the Forteo formulation 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. Use of the Bonsity formulation for more than 2 years during a patient's lifetime is not recommended. The North American Menopause Society (NAMS) recommends that use of parathyroid analogs in postmenopausal women be reserved for those patients with a high risk of fracture who do not have hypercalcemia, bone metastases, any bone tumor-predisposing disorder, or a history of skeletal irradiation.
For glucocorticoid-induced osteoporosis in adults at high risk of fracture.
Subcutaneous dosage
Adults
20 mcg subcutaneously once daily. Use of the Forteo formulation 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. Use of the Bonsity formulation for more than 2 years during a patient's lifetime is not recommended. Patients at high risk of fracture are defined as those with history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Supplement calcium and vitamin D if dietary intake is inadequate.
For the treatment of hypoparathyroidism†.
Subcutaneous dosage
Adults
Teriparatide has been investigated off-label for hypoparathyroidism, but the role of the drug for treatment of these patients is not established. Typical dosage used in open-label trials is 20 mcg subcutaneously once or twice daily. More study is needed to determine if teriparatide has a role in the treatment of these patients.
†Indicates off-label use
MAXIMUM DOSAGE
Adults
20 mcg/day subcutaneously for osteoporosis.
Geriatric
20 mcg/day subcutaneously for osteoporosis.
Adolescents
Safety and efficacy have not been established.
Children
Safety and efficacy have not been established.
Infants
Safety and efficacy have not been established.
DOSING CONSIDERATIONS
Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are necessary.
Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are necessary.
ADMINISTRATION
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Teriparatide solution should be clear and colorless.
Use of the Forteo formulation 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.
Use of the Bonsity formulation for more than 2 years during a patient's lifetime is not recommended.
Subcutaneous Administration
Administer subcutaneously only. Do not inject intramuscularly or intravenously.
Administer the first dose under circumstances where the patient can sit or lie down if symptoms of orthostatic hypotension occur.
Patients and/or caregivers who administer teriparatide should receive appropriate training and instruction on the proper use of the prefilled delivery device (pen) from a qualified health care professional.
Subcutaneous Administration (Forteo or Bonsity Pen)
Inject subcutaneously into the thigh or abdomen.
Lightly pinch a fold of skin; insert the needle at a 90-degree angle. Push in the pen injection button until it stops. Hold it in and count to 5 slowly. Wait until the count of 5 to make sure the correct dose is administered. Then pull the needle from skin.
Properly dispose of used pen needles.
Rotate administration sites with each injection to prevent lipodystrophy.
The pen should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients; reserve the use of any pen for 1 patient only.
Storage: Store the pen under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) at all times except when administering the product. Do not freeze. Do not use if the device has been frozen. Do not store the pen with the needle on, as the medication may leak out or air bubbles may form in the cartridge. Recap the delivery device when not in use to protect the cartridge from physical damage and light. During each use, time out of the refrigerator should be minimized; the dose may be delivered immediately following removal from the refrigerator. Each pen can be used for up to 28 days after the first injection. After 28 days, discard the pen, even if it still contains unused solution.
STORAGE
Generic:
- Avoid use of product if it has been frozen
- Discard 28 days after first use
- Discard product if it contains particulate matter, is cloudy, or discolored
- Protect from freezing
- Protect from light
- Refrigerate (between 36 and 46 degrees F)
FORTEO:
- Avoid use of product if it has been frozen
- Discard product if it contains particulate matter, is cloudy, or discolored
- Protect from freezing
- Protect from light
- Refrigerate (between 36 and 46 degrees F)
CONTRAINDICATIONS / PRECAUTIONS
General Information
Teriparatide is contraindicated in patients with a hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis.
New primary malignancy, osteogenic sarcoma, Paget's disease, radiation therapy
Rare cases of osteogenic sarcoma (osteosarcoma) have rarely been reported postmarketing in patients on teriparatide therapy; however, an increased risk of osteosarcoma was not detected in observational studies in humans. An increase in the incidence of osteosarcoma was observed during animal studies in male and female rats treated with teriparatide. Consider the potential risk of this new primary malignancy before treating patients with teriparatide. There are limited data assessing the risk of osteosarcoma beyond 2 years of teriparatide use. Use of teriparatide for more than 2 years during a patient's lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture. Avoid prescribing teriparatide to patients who are at an increased risk for osteosarcoma (i.e., those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses or lack of epiphyseal closure, or patients with prior external beam or implant radiation therapy involving the skeleton). Patients with bone metastases or a history of skeletal malignancies and those with metabolic bone disorders other than osteoporosis should also not receive treatment with teriparatide.
Hypercalcemia, hyperparathyroidism
Teriparatide is the amino-terminal fragment of parathyroid hormone and has actions similar to parathyroid hormone. Teriparatide may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with teriparatide. Measure serum calcium at least 16 hours after drug administration if indicated.
Hypercalciuria, nephrolithiasis
Teriparatide has not been studied in patients with active nephrolithiasis. In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. Use the drug with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.
Orthostatic hypotension
Teriparatide 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.
Pregnancy
Consider discontinuing teriparatide when pregnancy is recognized. There are no available data regarding the use of teriparatide in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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), and the drug produced mild growth retardation and reduced motor activity in rat offspring at subcutaneous doses equivalent to more than 120 times the human dose.
Breast-feeding
It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breastfed infant. Because of the potential for osteosarcoma shown with teriparatide in animal studies, advise patients that breast-feeding is not recommended during treatment.
Children, infants, neonates
The safety and efficacy of teriparatide have not been established in any pediatric population (adolescents, children, infants, neonates). The drug should not be prescribed in patients at an increased baseline risk of osteosarcoma which includes pediatric and young adult patients with open epiphyses. Therefore, teriparatide is not indicated for use in pediatric or young adult patients with open epiphyses.
ADVERSE REACTIONS
Severe
anaphylactic shock / Rapid / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
angioedema / Rapid / 0-1.0
calciphylaxis / Delayed / Incidence not known
osteogenic sarcoma / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
Moderate
hypercalcemia / Delayed / 1.0-10.0
hypertension / Early / 7.1-7.1
dyspnea / Early / 3.6-6.0
constipation / Delayed / 5.4-5.4
orthostatic hypotension / Delayed / 5.0-5.0
depression / Delayed / 4.1-4.1
antibody formation / Delayed / 2.2-3.0
angina / Early / 2.5-2.5
phosphaturia / Early / Incidence not known
hypercalciuria / Delayed / Incidence not known
hypomagnesemia / Delayed / Incidence not known
Mild
nausea / Early / 8.5-14.0
arthralgia / Delayed / 10.1-10.1
muscle cramps / Delayed / 1.0-10.0
rhinitis / Early / 9.6-9.6
asthenia / Delayed / 8.7-8.7
dizziness / Early / 8.0-8.0
headache / Early / 7.5-7.5
cough / Delayed / 6.4-6.4
pharyngitis / Delayed / 5.5-5.5
dyspepsia / Early / 5.2-5.2
diarrhea / Early / 5.1-5.1
rash / Early / 4.9-4.9
insomnia / Early / 4.3-4.3
vertigo / Early / 3.8-3.8
vomiting / Early / 3.0-3.0
syncope / Early / 2.6-2.6
diaphoresis / Early / 2.2-2.2
urticaria / Rapid / 0-1.0
injection site reaction / Rapid / Incidence not known
DRUG INTERACTIONS
Digoxin: (Minor) Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide increases serum calcium it should be used with caution in patients taking digoxin. Administering a single dose of teriparatide to patients with steady state digoxin levels did not alter the effect of digoxin on the systolic time interval.
PREGNANCY AND LACTATION
Pregnancy
Consider discontinuing teriparatide when pregnancy is recognized. There are no available data regarding the use of teriparatide in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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), and the drug produced mild growth retardation and reduced motor activity in rat offspring at subcutaneous doses equivalent to more than 120 times the human dose.
It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breastfed infant. Because of the potential for osteosarcoma shown with teriparatide in animal studies, advise patients that breast-feeding is not recommended during treatment.
MECHANISM OF ACTION
Mechanism of Action: Teriparatide is a recombinant amino terminal fragment of parathyroid hormone (PTH), comprised of the first 34 amino acids of PTH which produce most of its chief biologic effects. Endogenous PTH is the primary regulator of calcium and phosphate metabolism in the bone and kidney; it acts directly on the bone and kidney and also acts indirectly on the intestine to increase serum calcium concentrations. Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (i.e., increases serum calcium and decreases serum phosphorous.) Teriparatide binds to the same receptors as PTH and is known to exert effects identical to that of PTH on the bone and the kidney. Studies have shown teriparatide to be an effective treatment for patients with hypoparathyroidism.PTH and teriparatide stimulate bone formation and resorption and can increase or decrease bone mass, depending on the level of exposure. Continuous infusions and intermittent subcutaneous injections of these agents stimulate bone formation similarly but have different effects on bone resorption and bone mass. Continuous infusions result in persistent elevation of serum PTH and teriparatide concentrations which lead to greater bone resorption, while intermittent (i.e. once or twice daily) injections provide a transient increase in serum concentrations and preferentially stimulate osteoblastic activity over osteoclastic activity, resulting in a net stimulation of new bone formation, particularly on the trabecular, endocortical, endosteal, and periosteal bone surfaces.Teriparatide's anabolic effects manifest as in increase in skeletal mass, increase in the number of osteoblasts and osteoclasts allowing for an increase in bone remodeling, and an increase in bone strength. Osteoblasts have PTH receptors where teriparatide binds and stimulates bone-forming effects. Osteoclasts do not have PTH receptors, but appear to be activated by cytokines and other biochemical precursors that are released by stimulated osteoblasts. Teriparatide binds to the plasma-membrane receptors on osteoblasts and increases intracellular production of cyclic adenosine monophosphate (cAMP) and adenyl cyclase (AC). The release of cAMP and AC triggers osteogenesis, and cAMP prompts the release of genes that drive the accumulation of osteoblasts and osteogenesis. The net result of increased number of osteoblasts and increased osteogenesis is increased bone mass and bone strength.
PHARMACOKINETICS
Teriparatide is administered as a subcutaneous injection. Systemic clearance (approximately 62 L/hour in women and 94 L/hour in men) of teriparatide 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 absorption from the injection site. Peripheral metabolism of intact PTH, the 34 N-terminal amino acids, and, presumably, teriparatide, is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.
Affected cytochrome P450 isoenzymes and drug transporters: None
Subcutaneous Route
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. Pharmacokinetic data from another brand of injection (20-mcg dose) results in a Cmax of 109.5 +/- 62.8 pg/mL (mean +/- SD) at a median Tmax of 0.25 hours (0.12 minimum, 1.08 maximum). Concentrations decline to non-quantifiable within 3 hours.