Teriparatide (r-Human parathyroid hormone).
Each mL of Teriparatide [recombinant-human parathyroid hormone (1-34)] injection contains: Recombinant human parathyroid hormone (1-34) 250 mcg, succinic acid USP/NF 0.29 mg, sodium hydroxide USP/NF 0/05 mg, glycerol USP/NF 50 mg, m-cresol USP/NF 3 mg, and water for injection USP/NF.
Teriparatide (rDNA origin) 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.
Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Teriparatide injection is available as a clear and colorless solution.
Excipients/Inactive ingredients: Succinic acid, USP/NF, sodium hydroxide USP/NF, glycerol USP/NF, m-cresol USP/NF, water for injection USP/NF.
Pharmacology: Pharmacodynamics: Mechanism of Action:
Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Teriparatide is the active fragment (1-34) of endogenous human parathyroid hormone. Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts). Indirectly increasing the intestinal absorption of calcium and increasing the tubular re-absorption of calcium and excretion of phosphate by the kidney.
Pharmacodynamic Effects: Teriparatide is a bone formation agent to treat osteoporosis. The skeletal effects of Teriparatide depend upon the pattern of systemic exposure. Once daily administration of Teriparatide increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
Pharmacokinetics: Teriparatide is extensively absorbed after subcutaneous injection; peak plasma concentrations are reached after about 30 minutes. Absolute bioavailability is reported to be about 95%. Teriparatide is eliminated through hepatic and extra hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men). The volume of distribution is approximately 1.7 L/kg. The half-life of teriparatide is approximately 1 hr. When administered subcutaneously, which reflects the time required for absorption from the injection site. No metabolism or excretion studies with teriparatide have been reported but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.
Pharmacokinetics in Special Population: Teriparatide is extensively 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.
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.
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: Pharmacokinetic data in pediatric patients are not available.
Geriatric: 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 Insufficiency: No pharmacokinetic differences were identified in 11 patients with mild or moderate renal insufficiency [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. In 5 patients with severe renal insufficiency (CrCl <30 mL/min), the AUC and t½ 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.
Heart Failure: No clinically relevant pharmacokinetic, blood pressure, or pulse rate differences were identified in 13 patients with stable New York Heart Association Class I to III heart failure after the administration of two 20-mcg doses of teriparatide.
Hepatic Insufficiency: 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. No studies have been performed in patients with hepatic impairment.
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 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).
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture:
Teriparatide (rDNA origin) injection 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, teriparatide (rDNA origin) injection reduces the risk of vertebral and nonvertebral fractures.
Route of administration: Subcutaneous injection.
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture:
The recommended dose is 20 mcg subcutaneously once a day.
Patients and caregivers who administer Teriparatide (rDNA origin) injection should receive appropriate training and instruction on the proper use of the Teriparatide (rDNA origin) injection delivery device from a qualified health professional.
Pediatric: There is no experience in children. rhPTH (1-34) (teriparatide for injection) should not be used in pediatric patients or young adults with open epiphyses.
Geriatric: Dosage adjustment based on age is not required.
Missed Dose: If the patient misses a dose, use it as soon as remembered. If it is near the time of the next dose, skip the missed dose and resume the usual dosing schedule. Do not double the dose to catch up.
The safety and efficacy of Teriparatide (rDNA origin) injection have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 year during a patient’s lifetime is not recommended.
Administration: Teriparatide (rDNA origin) injection 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 teriparatide (rDNA origin) injection. Teriparatide (rDNA origin) injection should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit Teriparatide (rDNA origin) injection is a clear and colorless liquid. Do not use if solid particles appear or if the solution is cloudy or colored.
Signs and Symptoms: No cases of overdose were reported. 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 delayed hypercalcemia and risk of orthostatic hypotension. Nausea, vomiting, dizziness and headache can also occur.
Overdose experience based on post-marketing spontaneous report: There have been cases of medication error where the entire contents (up to 800 mcg) of the Teriparatide have been administered as multiple doses. 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 of Teriparatide have been reported.
Overdose Management: There is no specific antidote for Teriparatide. Treatment of suspected overdose should include transitory discontinuation of teriparatide, monitoring of serum calcium and implementation of appropriate supportive measures, such as hydration.
rhPTH (1-34) (Teriparatide for Injection) is contraindicated in the following patients: Hypersensitivity to teriparatide or to any of the excipients of this product. Pre-existing hypercalcaemia. Severe renal impairment. Metabolic bone diseases other than primary osteoporosis (including Hyperparathyroidism and Paget’s disease of bone). Unexplained elevations of alkaline phosphatase. Prior external beam or implant radiation therapy to the skeleton. Patients with skeletal malignancies or bone metastases should be excluded from treatment with teriparatide.
Teriparatide has not been studied in patients with active urolithiasis in reported clinical trials.
Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In reported short term clinical studies with teriparatide injection, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved with a few minutes to a few hours. When transient orthostatic hypotension occurred, if happened within the first several doses, was relieved by placing subjects in a reclining positions, and did not preclude continued treatment in a reported study of 15 healthy people administered digoxin daily to steady state, a single dose of teriparatide 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 teriparatide transiently increases serum calcium, Teriparatide should be used with caution in patients taking digitalis. In nomocalcaemic patients, slight and transient elevations of serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of Teriparatide.
Routine calcium monitoring during therapy is not required.
Therefore, if any blood samples are taken from a patient, this should be done at least 16 hours after the most recent Teriparatide injection.
Teriparatide may cause small increases in urinary calcium excretion.
Limited information is available to evaluate safety in patients with hepatic, renal and cardiac disease.
No clinically important adverse renal effects were observed in reported 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 reported. Caution should be exercised in patients with moderate renal impairment.
Teriparatide therapy was associated with increased incidence of elevated uric acid, with the incidence being highest in patients with moderately impaired renal function and in those receiving teriparatide 40 mcg/day. Even so, adverse event data did not suggest an increased incidence of gout or arthralgia or of nephrolithiasis in teriparatide treated patients with normal, mild or moderate renal impairment.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, transient orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided.
Use in Children: The safety and efficacy of Teriparatide (rDNA origin) have not been established in pediatric populations. Teriparatide is not indicated for use in pediatric patients.
Use in the Elderly: Of the patients receiving Teriparatide (rDNA origin) 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 Teriparatide 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 Teriparatide as compared with younger patients. Nonetheless, as with many medications, elderly patients may have greater sensitivity to the adverse effects of Teriparatide.
Use in Pregnancy:
Pregnancy Category C: Reported studies in rabbits have shown reproductive toxicity. The potential risk for humans is unknown. Given the indication, Teriparatide should not be used during pregnancy.
In pregnant rats given subcutaneous teriparatide doses up to 1000 mcg/kg/day, there were no mortality. 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 dose based on surface area, mcg/m2). The effect of teriparatide treatment on human fetal development has not been studied. Teriparatide (rDNA origin) is not indicated for use in pregnancy.
Use in Lactation:
Because Teriparatide (rDNA origin) 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.
The following convention has been used for the classification of the adverse reactions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to < 1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). The most commonly reported adverse events in patients treated with teriparatide are nausea, pain in limb, headache and dizziness. (See Tables 1, 2 and 3.)
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Teriparatide increases serum uric acid concentrations. However, the hyperuricemia does not result in an increase in gout, arthralgia or urolithiasis.
Antibodies that cross-reacted with teriparatide were detected in women receiving teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions, allergic reactions, effects on serum calcium, or effects on bone mineral density (BMD) response.
There have been spontaneous reports of the following adverse reactions. (See Table 4.)
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A single teriparatide (rDNA origin) injection 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 teriparatide (rDNA origin) injection may transiently increase serum calcium, teriparatide (rDNA origin) injection should be used with caution in patients taking digoxin.
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.
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.
Protect from light and moisture.
Store between 2°C to 8°C. Do not freeze.
Shelf-Life: Not more than 24 months from date of manufacture when stored at temperature 2-8°C.
Instruction for Use Pen Injector: Preparing the Pen:
1. Wash hands before preparing the pen for use.
2. Remove the pen injector from the refrigerator.
3. Remove the pen cap by pulling it off.
4. A number of medicines come in pen delivery devices. Check the label on the pen before
each use to make sure the patient is using pen injector.
5. Look at the Teriparatide medicine in the cartridge. It should be clear and colorless, and it should not have particles in it. If it is not clear and colorless, or if it has particles, do not use it.
6. Use an alcohol swab to wipe the rubber seal on the end of the pen.
Attaching the Needle:
1. Always use a new needle for each injection. Do not store the pen with the needle attached.
Storing the pen with the needle attached may let Teriparatide leak from the pen, and air bubbles can form in the cartridge.
2. Pull off the paper tab from the outer needle shield and throw the paper tab away.
3. Attach the capped needle to the end of the pen by pushing it on and turning it clockwise (to the right). Do not over-tighten the needle since it must be removed after the injection.
4. Hold the pen with the needle pointing up and remove the outer needle shield. Keep the outer needle shield because it will be needed to remove the needle after the injection is finished.
5. Pull off the inner needle shield and throw it away.
Priming the Pen: Always use a new needle for every injection.
The pen must be primed before every injection.
The patient must prime the pen to make sure the medicine is flowing and that the patient is receiving the correct dose. Priming removes air bubbles that might affect the dose. Small air bubbles may collect in the Teriparatide cartridge during normal use.
Note: A small air bubble may stay in the cartridge when the patient has finished the priming step. If patient has properly primed the pen, this small air bubble will not harm the patient or affect Teriparatide dose.
The very small amount of the prime dose does not affect the total supply of 28 days of therapy that the pen will deliver.
1. Turn the dose knob anti-clockwise (to the left) until the number "2" in the dose window.
2. With the arrow and number "2" in the dose window in line, hold the pen with the needle pointing up. Tap the clear cartridge holder gently with the finger so any air bubbles collect near the top.
3. Using the thumb, if possible, push in the blue injection button all the way and keep pressing.
Continue to hold the blue injection button firmly and count s-1-o-w-1-y to 5. The patient should see either a few drops or a tiny stream of Teriparatide come out of the tip of the needle. If nothing comes out of the tip of the needle, repeat the "Priming the Pen" instructions.
4. Number "0" and arrow notch are in line in the dose window. This means that the priming is complete.
Setting the Dose: The numbers in the dose window do indicate the size of the dose. Number "2" means 20 μL, number "4" means 40 μL etc.
1. Turn the dose knob anti-clock clockwise (to the left) until the patient sees the arrow notch and number "8" are in line in the dose window.
2. When the number "8" and arrow notch are in line, set the 20-mcg dose and the pen is "ready to inject."
Injecting the Dose: Make injections just below the surface of the skin (the subcutaneous tissue).
1. Prepare the skin for the injection as instructed by the health care professional.
2. Lightly hold a fold of skin as shown below, and push the needle straight into the skin.
The skin may need to be pinched up to avoid a deep injection into a muscle (intramuscular), especially in the thigh area. Ask the health care professional for more instructions about injection technique and changing sites (rotation).
3. Still see the number "8" and arrow notch are in line in the dose window. Inject the Teriparatide by using the thumb, if possible, to push in the blue injection button all the way.
4. Continue to hold down the blue injection button firmly and count s-l-o-w-l-y to 5 to ensure that the Teriparatide has been completely injected into the skin. Remove the needle from the skin when finished counting.
5. When the injection is complete, the patient must see number "0" and arrow notch are in line in the dose window. This tells that the injection button has been pushed in all the way and that the full dose has been injected.
After an Injection:
1. Carefully replace the outer needle shield as instructed by the health care professional.
2. Remove the capped needle by turning it counterclockwise (to the left). Place the used needle in a puncture-resistant disposable container and properly throw it away as directed by the health care professional.
3. Replace the cap on the pen.
4. Store the pen injector in the refrigerator at 36°F to 46°F (2°C to 8°C) at all times. The patient should inject Teriparatide right after the patient takes the pen out of the refrigerator. Put the pen back into the refrigerator right after use.
5. The patient can use the pen injector for up to 28 days including the first injection from the pen. After 28 days, throw away the pen injector, even if it is not completely empty. Throw away the pen as directed by the health care professional.
6. Never share a pen injector.
7. Do not freeze the pen injector. Do not use Teriparatide if it has been frozen.
8. Do not use the pen injector after the expiration date printed on the carton and pen label.
9. Do not store or throw away the pen with a needle attached.
H05AA02 - teriparatide ; Belongs to the class of parathyroid hormones and analogues. Used in the management of calcium homeostasis.
Inj (multi-dose USP type-I glass cartridge) 750 mcg/3 mL (clear and colorless) x 1's.