Treatment of postmenopausal osteoporosis with 20 mcg teriparatide daily doses decreases the risk of vertebral fractures and non-vertebral fractures significantly.

Teriparatide treatment increases the bone mineral density and is a potentially
effective therapy for osteoporosis in men.

In high fracture risk patients with Glucocorticoid-induced osteoporosis,
teriparatide significantly increases bone mineral density than that
achieved by bisphosphonates.

In Indian patients OSTEOTIDE significantly increased the percentage of change
in lumbar spine T-score (P<0.001), bone mineral content (P<0.001) and bone area.

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 reabsorption of calcium and excretion of phosphate by the kidney.
The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-a-day administration of teriparatide increases apposition of new bone on trabecular, endocortical, and periosteal bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. Anabolic effects of teriparatide manifest as an increase in skeletal mass, bone strength and an increase in markers of bone formation and resorption.

Pharmacokinetics

Teriparatide is extensively absorbed after subcutaneous injections; 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 hour 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

Geriatrics: No differences in teriparatide pharmacokinetics were detected with respect to age (range 31 to 85 years). Dosage adjustments based on age are not required.

Pediatric: Pharmacokinetic data in pediatric patients are not available.

Gender: Although systemic exposure to teriparatide was approximately 20-30% lower in men than among women, the recommended dose for both the genders is 20 µg/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] 30-72 mL/min) when a single dose of teriparatide was administered. In 5 patients with severe renal insufficiency (CrCl <30 mL/min), the AUC and t1/2 of teriparatide increased by 73% and 77% respectively. Maximum serum concentration of teriparatide did not increase. No studies have been reported 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 µg 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 reported in patients with hepatic impairment.

Indications and usage

OSTEOTIDE is indicated:

• For the treatment of postmenopausal women with osteoporosis at high risk for fracture,
patients who have failed or are intolerant to other available osteoporosis therapy.

• To increase 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.

• For the treatment of men and women with osteoporosis associated with sustained systemic
glucocorticoid therapy who are at high risk for fracture.

Dosage and administration

The recommended dose of OSTEOTIDE is 80 µL containing 20 µg teriparatide to be administered once daily by subcutaneous injection in the thigh or abdomen.

OSTEOTIDE should be administered initially in an environment in which the patient can assume a supine or sitting position if orthostatic hypotension occurs.
The maximum total duration of treatment with OSTEOTIDE is 2 years. In addition to OSTEOTIDE, patients should receive calcium and vitamin D supplements if dietary intake is inadequate.

Following cessation of OSTEOTIDE therapy, patients may be continued on other osteoporosis therapies.

Use in renal impairment: OSTEOTIDE should not be used in patients with severe renal impairment. OSTEOTIDE should be used with caution in patients with moderate renal impairment.

Use in hepatic impairment: No data are available on patients with impaired hepatic function.

Contraindications

OSTEOTIDE is contraindicated in the following patients:

• Hypersensitivity to teriparatide or to any of the excipients of this product
• Pregnancy and lactation
• Pre-existing hypercalcemia
• Severe renal impairment
• Metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism
and Paget's disease of the bone)or glucocorticoid-induced osteoporosis
• Unexplained elevations of alkaline phosphatase
• Prior external beam or implant radiation therapy to the skeleton
• Patients with skeletal malignancies or bone metastases

Warnings and precautions

The 2 years duration of treatment should not be exceeded.
Teriparatide has not been studied in pediatric populations. Pediatric patients have increased baseline risk for osteosarcoma and therefore OSTEOTIDE should not be used in pediatric patients or young adults with open epiphyses.

General:
Teriparatide has not been studied in patients with active urolithiasis in reported clinical trials. It should be used with caution in patients with active or recent urolithiasis because of its potential to exacerbate this condition.

Hypotension: Isolated episodes of transient orthostatic hypotension were observed in short-term clinical studies with teriparatide injection. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. Transient orthostatic hypotension occurred, during the initial doses, and was relieved by placing subjects in a reclining position. However, it did not preclude continued treatment. No studies on its effects on the ability to drive and use machines have been reported. These patients should refrain from driving or the use of machines until symptoms have subsided.

Digoxin: In a reported study of 15 healthy people who were 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.

Serum calcium: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a peak 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 on patients with hepatic, renal, and cardiac disease.

Renal function: 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.

Serum uric acid: Teriparatide therapy was associated with increased incidence of elevated uric acid, the incidence being highest in patients with moderately impaired renal function and in those who were receiving teriparatide 40 µg/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.

Use in the elderly: No overall differences in safety or effectiveness were observed between elder and younger subjects. Dosage adjustment based on age is not required.

Pediatric use: The safety and efficacy of teriparatide have not been established in pediatric population. OSTEOTIDE should not be prescribed in pediatric and young adult patients with open epiphyses who are at an increased baseline risk of osteosarcoma.

Use during pregnancy and lactation
Teriparatide is classified under pregnancy category C. Adequate well controlled studies are not available on pregnant women. Animal studies have shown that teriparatide exhibits reproductive toxicity. OSTEOTIDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether teriparatide is secreted into milk. Because of its potential for tumorigenicity, a decision should be made whether to discontinue nursing or to discontinue OSTEOTIDE, depending on the importance of the drug to the mother.

Overdose

Signs and symptoms: No cases of overdose were reported. Teriparatide has been administered in single dose of up to 100 µg and in repeated doses of up to 60 µg/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 reports: There have been cases of medication error where the entire contents (up to 800 µg) of the teriparatide pen have been administered as a single dose. Transient events reported include 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.

Adverse reactions

The most commonly reported adverse events in patients treated with teriparatide are nausea, pain in limb, headache and dizziness. The following convention has been used for the classification of the adverse reactions: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 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). An overview of adverse events reported with teriparatide during clinical trials conducted by the innovator is presented in Tables I, II and III.

Table I: Very Common Adverse Events (>1/10)

Table II: Common Adverse Events (>1/100 to <1/10)

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. The following spontaneous adverse reactions have been reported:

Evidences on Teriparatide

Teriparatide decreases the risk of vertebral and non-vertebral fractures and increases vertebral, femoral, and total-body BMD in postmenopausal women.
http://www.nejm.org/doi/full/10.1056/NEJM200105103441904

Teriparatide treatment increases the BMD in men with osteoporosis.
http://www.osteos.org.lb/membership/pdf/PTH-2-2003.pdf

Teriparatide is superior to alendronate in the treatment of glucocorticoid-induced osteoporosis.
http://www.ncbi.nlm.nih.gov/pubmed/19877063

Teriperatide is safe and effective in postmenopausal women who are on concomitant glucocorticoid therapy.
http://www.ncbi.nlm.nih.gov/pubmed/22247365

OSTEOTIDE is safe and effective in increasing bone mineral density in postmenopausal Indian women with osteoporosis.
http://www.japi.org/june_2008/O-418.pdf