Zotide (Teriparatide ) Monograph

Table of Content

Introduction

Osteoporosis is a largely asymptomatic, widespread disease worldwide which is characterised by a decrease in bone mass and microarchitectural alterations. This in turn results in bone fragility and increased risk of fractures.1

The most common osteoporotic fractures are those of the vertebrae, proximal femur and distal forearm. Fractures may be followed by full recovery or by chronic pain, disability and death. In particular, hip fractures result in 8 - 36 percent excess mortality within one year. Hip fractures are associated with a 2.5-fold increased risk of future fractures.2

Burden of Osteoporosis

As per the Indian Osteoporosis Foundation factsheet, 1 in 3 women and 1 in 5 men over the age of 50 will experience an osteoporotic fracture. Worldwide, there is one osteoporotic fracture in every three seconds. In Europe, India, Japan and the USA alone, there are an estimated 125 million people with osteoporosis. The number of people living with osteoporosis in all regions of the world is set to increase dramatically.3

Osteoporotic fractures cause an annual global loss of 5.8 million healthy life years to disability. After a hip fracture, 40% of individuals cannot walk independently, and 80% cannot perform basic activities independently. 10-20% of hip fracture sufferers require permanent nursing home care after the incident.3

Osteoporosis: Indian Facts and Figures

Osteoporosis is greatly under-diagnosed and under-treated in Asia, even in the most high-risk patients who have already fractured. In the most populous countries like China and India, the majority of the population lives in rural areas, where hip fractures are often treated conservatively at home instead of by surgical treatment in hospitals.4

Several studies have reported prevalence of osteoporosis ranging from 8% to 62% in Indian women of different age groups.5 It is also observed that in Indians, osteoporotic fractures occur 10-20 years earlier as compared to West. Some studies in India have also shown that the bone mineral density values in Indian population were 15% lower than the western population.6

Treating Osteoporosis: Recent and Emerging Trends

The target of osteoporosis treatment is to prevent fractures by correcting the imbalance in the bone remodelling process which affects bone strength, bone geometry and microarchitecture. Accelerated bone remodelling constitutes an additional risk factor for fracture when bone resorption exceeds bone formation. By reducing or reversing the negative balance in bone remodelling, osteoporosis therapies can preferentially modulate bone resorption and formation.7

Oral bisphosphonates are considered first-line pharmacological therapy for most post-menopausal women at high risk for fracture in the absence of specific contraindications.8 Bisphosphonates inhibit bone resorption and improves the bone remodelling balance, thereby reducing the rate of bone turnover, with a trend towards positive bone balance. This in turn helps in preserving the microarchitecture and lowers the incidence of osteoporotic fractures.7

Teriparatide (human parathyroid hormone 1-34, of recombinant DNA origin), an anabolic agent given once daily, represents a new therapeutic option for osteoporosis. In contrast to anti-resorptive agents, teriparatide increases bone formation earlier and to a greater magnitude than resorption. This further results in a positive bone balance, an increase in bone mineral density (BMD), an improvement in bone microarchitecture and strength, and a reduction in fracture incidence.7

Pathophysiology of Osteoporosis – Role of PTH

Osteoporosis results due to a dysfunction of physiological bone turnover and cells in bone by endocrine and/or autocrine/paracrine factors, negatively affecting peak bone mass and/or skeletal homeostasis. One such factor that plays an important role in bone metabolism isparathyroid hormone (PTH). PTH is an 84-amino acid polypeptide that plays a central role in regulating calcium-phosphate metabolism and its production increases in response to low serum calcium levels.9

A continuous hyper-secretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. PTH mediates its action through its following 3 mechanisms:10

  • Increases the osteoclast mediated bone resorption (Figure 1)
  • Increases the renal tubular calcium reabsorption (Figure 2)
  • Stimulates the renal calcitriol production thereby indirectly increasing intestinal calcium absorption
Figure 1: Osteoblasts and osteoclasts are closely related in determining bone formation and bone resorption (bone turnover) that maintain the quantitative and qualitative characteristics of bone

Figure 2: PTH action in calcium regulation

Figure 3: Role of PTH

Use of PTH Analogue in Osteoporosis Treatment

Endogenous PTH is an 84 amino acid peptide (PTH 1–84) that together with active fragments such as PTH 1–34 (teriparatide) has contrasting effects on bone, depending upon the length of exposure.11 The prolonged elevated levels of PTH found in normocalcemic hyperparathyroidism typically result in reduced BMD and increased fracture risk.12 Research has shown that bone formation occurs soon after PTH is administered because osteoblast formation is increased and osteoblast apoptosis is inhibited, which results in an increase in bone turnover and formation (Figure 3).13

Thus, the anabolic properties of PTH 1-34 which can be synthesized through recombinant DNA technology seems to exert positive effects on bone volume and microarchitecture when administered at a low dose and intermittently.9

The anabolic actions of PTH involve direct effects on osteoblasts and indirect effects mediated by activation of skeletal growth factors (IGF-I) and inhibition of growth factor antagonists, such as sclerostin. PTH enhances the number and the activation of osteoblast by increasing osteoblast proliferation and differentiation, decreasing osteoblast apoptosis and reducing the negative effects of peroxisome proliferator activator (PPAR) γ receptor on osteoblast differentiation.9

Spotlight on Zotide

Description

ZOTIDE contains Teriparatide, a biosynthetic (rDNA origin) peptide fragment of the human parathyroid hormone (PTH) which is a regulator of bone metabolism. It is produced by using a strainof Escherichia coli employing recombinant rDNA technology. Its sequence is identical to that of 34N-terminal amino acids (the biological active region) of the endogenous 84-amino acid human parathyroid hormone (Figure 4). It is a water-soluble protein with a molecular weight of 4117.8 daltons.14

Figure 4: Human parathyroid hormone consists of 84 amino acids. Teriparatide represents the N-terminal portion of the first 34 amino acids. This fragment is believed to confer all the biological actions of the full-length peptide

Clinical Pharmacology

Mechanism of Action

Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidneys. Teriparatide isthe active fragment (1–34) of endogenous humanparathyroid 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 renal tubular reabsorption of calcium and excretion of phosphate by the kidneys. 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.14

Teriparatide is a bone formation agent used to treat osteoporosis. Its skeletal effects depend upon the pattern of systemic exposure. Once-daily administration of teriparatide increases the apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

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 4-6 hours (median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16-24 hours after each dose. (check the above para its not in pdf)

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.14

Distribution: 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.14

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.14

Metabolism: No metabolism or excretion studies with teriparatide have been reported but the peripheral metabolism of the parathyroid hormone is believed to occur predominantly in the liver and kidneys.14

Excretion: Teriparatide is eliminated through hepatic and extra-hepatic clearance (approximately 62 l/hr in women and 94 l/hr in men).14

Special Population14

  • Paediatric Patients: Pharmacokinetic data in pediatric patients are not available.
  • Geriatric Patients: No age-related differences in teriparatide pharmacokinetics were detected (range31 to 85 years). Dosage adjustment based on age is not required.
  • 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 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.
  • Hepatic Impairment: No studies have been performed in patients with hepatic impairment. Nonspecific 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.

Zotide – Focus on Clinical Efficacy 

Several studies have assessed the clinical efficacy of teriparatide in severe osteoporosis.

Effects of Teriparatide Treatment on Bone Health Parameters15

To gain insight into how teriparatide affects various bone health parameters, the effects of teriparatide treatment was assessed using standard DXA technology and two newer technologies, high resolution MRI and finite element analysis of quantitative CT scans.

In a phase-4, open-label study, by Kleerkoper et al, post-menopausal women with severe osteoporosis received 20 mg/day.

Assessments

  • Changes in areal BMD (in g/cm2) at the radius,spine, and hip on DXA.
  • Changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans.
  • Changes in bone microarchitecture at the radius on high-resolution MRI.
  • Estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans.
  • Changes in bone turnover markers in serum.

Results

Vertebral outcomes

  • Significant increases were seen in volumetric BMD at the lumbar spine and in both bone compartments at month eighteen and at end point.
  • Lumbar spine bone strength, overall and in both bone components, was significantly increased from baseline at month eighteen and the end point (Figure 5).
Figure 5: Vertebral outcomes for month eighteen completers (full-set analysis). The whiskers indicate the 95% CI

Figure 6: Outcomes for month-eighteen completers (full-set analysis). The whiskers indicate the 95% CI

Hip outcomes

  • At eighteen months and at end point, the volumetric BMD for the total hip was significantly higher than baseline (p<0.05).
  • This increase was significantly higher in the trabecular area of the hip as compared to baseline at eighteen months and the end point (p<0.001).
  • Total hip strength was also significantly improved at month eighteen (p<0.05) (Figure 6).

Areal BMD

  • Significant increases in areal BMD, as assessed with DXA were seen in the lumbar spine (p<0.001) and femoral neck (p<0.05) skeletal sites, at months eighteen and twenty-four and at the end point (Figure7).
 Figure 7: Change in areal BMD. The whiskers indicate the 95% CI

Biochemical Markers of Bone Turnover

  • Serum procollagen type 1 N-terminal propeptide (P1NP):

o   Teriparatide-treated subjects had significantly greater levels of serum procollagen type 1 N-terminal propeptide (P1NP) as compared to CTX (p<0.001 compared with baseline) at all time points measured.

o   This is consistent with an osteoanabolic action of teriparatide that results initially in bone modelling followed by an increase in bone remodelling.

o   P1NP concentrations remained elevated after twenty-four months of teriparatide treatment, indicating continued stimulation of new bone formation.

o   Changes in serum P1NP at month three correlated with the increase in estimated vertebral strength at month eighteen (p=0.04)

  • Serum carboxy-terminal cross-linking telopeptide of collagen type 1 (CTX):

o   Serum carboxy-terminal cross-linking telopeptide ofcollagen type 1 (CTX) levels were also significantly greater compared with baseline.

Safety

·         The most common adverse events seen include arthralgia, muscle spasms and diarrhoea, insomnia, headache, falls, and decreased weight.

·         In 14% of the patients, an adverse event resulted in discontinuation.

Conclusion

·         Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip.

·         Estimated vertebral and femoral strength also increased.

·         These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide.

Effect of Teriparatide on Fracture Risk Reduction, Back Pain and Health Related Quality of Life16

A European study across 8 countries assessed the effectiveness of teriparatide in post-menopausal women with osteoporosis treated for up to 18 months. A total of 1,648 post-menopausal women were put on teriparatide treatment. Of these, 91.9 % had reported a fracture after the age of 40. A sustained fragility fracture within the 12 months prior to starting teriparatide treatment, was reported by approximately 48% of the women.

Results

Fracture Incidence

  • The overall fracture rate was 821/10,000 patient-years, with 138 (8.8%) women sustaining a total of 168 incident fractures during follow-up.
  • The number of patients who had at least one fracture during teriparatide treatment decreased significantly with time. A decrease of 47% in the odds of fracture was observed in the last 6-month period as compared to the first six months. (P<0.005).
  • During the 12–18 months, period the fractureincidence per 10,000 patient-years of 1,113 in thefirst 6 months decreased to 583. (Figure 8).
Figure 8: Number and percent patients with incident fractures in each 6-month period

Back Pain

  • Mean back pain VAS was reduced by 25.8 mm at end point, the largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort.

HRQoL

  • The Health-Related Quality of Life (HRQoL) was measured using the European Quality of Life Questionnaire.
  • There was a significant increase of 13 mm at 18 months in adjusted mean EQ-VAS values from baseline (Figure 9).
  • The improvement in the five domains of the European Quality of Life Questionnaire (EQ-5D) assessed –namely mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were significant.
Figure 9:  Adjusted change in back pain from baseline: 100 mm VAS

Conclusion:

  • Post-menopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18- month treatment period.
  • This was associated with a clinically significant improvement in HRQoL.

Zotide Prescribing Information

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Teriparatide Injection for Subcutaneous Use Only (Recombinant Human Parathyroid Hormone or rhPTH1-34)

ZOTIDE

POTENTIAL RISK OF OSTEOSARCOMA

In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumour) 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 teriparatide only to patients for whom potential benefits are considered to outweigh the potential risk.

Teriparatide should not be prescribed for patients at increased baseline risk for osteosarcoma (including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, paediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton).

Composition

ZOTIDE

Each cartridge contains:

Teriparatide ……………………. 750 mcg/3 ml

Water for injection, IP……q.s.

Excipients: Glycerol IP, Succinic acid, Meta-cresol, Sodium hydroxide IP

Dosage Form

Injection (Multi-dose cartridge for subcutaneous injection containing 28 doses).

Description

Teriparatide, a biosynthetic (rDNA origin) peptide fragment of the human parathyroid hormone (PTH), is a regulator of bone metabolism. It is produced by using a strain of Escherichia coli employing recombinant DNA technology. Its sequence is identical to that of 34 N-terminal amino acids (the biological active region) of the endogenous 84-amino acid human parathyroid hormone. It is a water-soluble protein with a molecular weight of 4117.8 daltons.

Pharmacology

Pharmacodynamics

Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidneys. 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 kidneys. 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.

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.

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.

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: 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.

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: No metabolism or excretion studies with teriparatide have been reported but the peripheral metabolism of the parathyroid hormone is believed to occur predominantly in the liver and kidneys.

Excretion: Teriparatide is eliminated through hepatic and extra-hepatic clearance (approximately 62 l/hr in women and 94 l/hr in men).

Special Population

  • aediatric Patients: Pharmacokinetic data in pediatric patients are not available.
  • Geriatric Patients: No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years). Dosage adjustment based on age is not required.
  • 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 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.
  • Hepatic Impairment: No studies have been performed in patients with hepatic impairment. Nonspecific 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.

Indication

ZOTIDE is indicated for the treatment of patients with severe osteoporosis.

Dosage and Administration

ZOTIDE cartridge should be used with the ZOTIDE Delivery Device-Pen and ZOTIDE Pen Needles. The recommended dose of ZOTIDE is 80 μl containing 20 mcg teriparatide to be administered once daily by subcutaneous injection in the thigh or abdomen. There are no data available on the safety or efficacy of intravenous or intramuscular injection of ZOTIDE. ZOTIDE should be administered initially in an environment in which the patient can assume a supine or sitting position if orthostatic hypotension should occur.

ZOTIDE is a clear and colourless liquid. Do not use if solid particles appear or if the solution is cloudy or coloured. Patients and caregivers who administer ZOTIDE should receive appropriate training and instruction on the proper use of the ZOTIDE delivery device from a qualified health professional.

The maximum total duration of treatment with ZOTIDE should be 2 years. The 24-month course of ZOTIDE should not be repeated over a patient's lifetime. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

Following cessation of ZOTIDE therapy, the patients may be continued on other osteoporosis therapy.

Contraindications

  • Hypersensitivity to teriparatide or any of the excipients of this product. Reactions have included angioedema and anaphylaxis
  • Pregnancy and breast-feeding
  • Pre-existing hypercalcaemia
  • Severe renal impairment
  • Metabolic bone diseases (including hyperparathyroidism and Paget’s disease of the bone) other than primary osteoporosis or glucocorticoid-induced osteoporosis
  • Unexplained elevations of alkaline phosphatase
  • Prior external beam or implant radiation therapy to the skeleton
  • Patients with skeleton malignancies or bone metastases should be excluded from treatment with teriparatide

Warnings and Precautions

General

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. Teriparatide 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.

Treatment Duration

The safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide. 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 teriparatide

Metabolic Bone Diseases

Patients with metabolic bone diseases other than osteoporosis should not be treated with teriparatide.

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 hypertension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment.

Urolithiasis or Pre-existing Hypercalciuria

In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo Teriparatide has not been studied in patients with active urolithiasis in reported clinical trials. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered.

Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

Hypercalcaemia and Hypercalcaemic Disorders

In normo-calcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. 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. Therefore, if any blood samples are taken from a patient, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during the therapy is not required.

Teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with teriparatide because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with teriparatide.

Teriparatide may cause small increases in the urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials.

Ability to Drive

Teriparatide has no or negligible influence on the ability to drive and use machines. 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.

Drug Interactions

Digoxin

In a study of 15 healthy people administered digoxin daily to the 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 hypercalcaemia may predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium, teriparatide should be used with caution in patients taking digitalis.

Hydrochlorothiazide

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.

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.

Renal Impairment

In 5 patients with severe renal insufficiency (CrCl< 30 ml/min), the AUC and T1/2 of teriparatide was increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. Caution should be exercised in patients with moderate renal impairment.

Hepatic Impairment

No studies have been reported in patients with hepatic impairment.

Pregnancy

Pregnancy Category C

Teriparatide is contraindicated for use during pregnancy. There are no adequate and well-controlled studies of teriparatide 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. Teriparatide should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

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 foetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneousteriparatide during organogenesis at doses 16 to 540 times the human dose, the foetuses 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).

Lactation

Teriparatide is contraindicated for use during breast-feeding. However, 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.

Women of childbearing potential / Contraception in females

Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued.

Paediatric Use

The safety and efficacy of teriparatide have not been established in any paediatric population. Teriparatide should not be prescribed in patients at an increased baseline risk of osteosarcoma which include paediatric and young adult patients with open epiphyses. Therefore, teriparatide is not indicated for use in paediatric or young adult patients with open epiphyses.

Geriatric Use

Dosage adjustment based on age is not required. In a clinical trial, no overall differences in safety or effectiveness were observed between elderly subjects (>65 years) 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.

Undesirable Effects

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. The most commonly reported adverse reactions in patients treated with teriparatide are nausea, pain in limb, headache and dizziness.

The adverse reactions associated with the use of teriparatide in osteoporosis clinical trials and post-marketing exposure are summarised in the table below. The following convention has been used for the classification of 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).

Table: Adverse reactions associated with the use of teriparatide in osteoporosis clinical trials and post-marketing exposure

Blood and lymphatic system disorders

Common: Anaemia

Immune System Disorder

Rare: Anaphylaxis

Metabolism and nutrition disorders

Common: Hypercholesterolaemia

Uncommon: Hypercalcaemia greater than 2.76 mmol/L, hyperuricaemia

Rare: Hypercalcaemia greater than 3.25 mmol/L

Psychiatric disorders

Common: Depression

Nervous system Disorders

Common: Dizziness, headache, sciatica, syncope, insomnia

Ear and labyrinth Disorders

Common: Vertigo

Cardiac Disorders

Common: Palpitations

Uncommon: Tachycardia

Vascular Disorders

Common: Hypotension, hypertension, angina pectoris

Respiratory, thoracic and mediastinal Disorders

Common: Dyspnoea, rhinitis, cough increased, pharyngitis, pneumonia

Uncommon: Emphysema

Gastrointestinal Disorders

Common: Nausea, vomiting, hiatus hernia, gastro-oesophageal reflux disease, constipation, diarrhea, dyspepsia, gastrointestinal disorder

Uncommon: Haemorrhoids

Skin and subcutaneous tissue Disorders

Common: Sweating increased, rash

Musculoskeletal and connective tissue Disorders

Very common: Pain in limb

Common: Muscle cramps, neck pain

Uncommon: Myalgia, arthralgia, back cramp/pain*

Renal and urinary Disorders

Uncommon: Urinary incontinence, polyuria, micturition urgency, nephrolithiasis

Rare: Renal failure/impairment

General disorders and administration site conditions

Common: Fatigue, chest pain, asthenia, mild and transient injection site events, including pain, swelling, erythema, localised bruising, pruritus and minor bleeding at injection site

Uncommon: Injection site erythema, injection site reaction

Rare: Possible allergic events soon after injection: acute dyspnoea, oro/facial oedema, generalised urticaria, chest pain, oedema (mainly peripheral)

Investigations

Uncommon: Weight increased, cardiac murmur, alkaline phosphatase increase

Description of Selected Adverse Reactions

In clinical trials the following reactions were reported at a ≥ 1 % difference in frequency from placebo: vertigo, nausea, pain in limb, dizziness, depression, dyspnoea.

Teriparatide increases serum uric acid concentrations. In clinical trials, 2.8 % of teriparatide patients had serum uric acid concentrations above the upper limit of normal compared with 0.7 % of placebo patients. However, the hyperuricaemia did not result in an increase in gout, arthralgia, or urolithiasis.

In a large clinical trial, antibodies that cross-reacted with teriparatide were detected in 2.8 % of 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.

Teriparatide increased serum uric acid concentrations. In clinical trials, 3% of teriparatide 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.

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.

Post-marketing Experience

The following adverse reactions have been identified during postapproval use of teriparatide. 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 teriparatide use is unclear.

Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with teriparatide use.

Adverse events reported since market introduction that were temporally (but not necessarily causally) related to teriparatide 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

If you experience any side-effects, talk to your doctor or pharmacist. You can also report side-effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Incidents of overdose in humans have not been reported in clinical trials.

Signs and symptoms

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 overdosage that might be expected include delayed hypercalcaemia and risk of orthostatic hypotension. Nausea, vomiting, dizziness and headache can also occur.

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.

Overdose experience based on post-marketing spontaneous reports

In post-marketing spontaneous reports, there have been cases of medication error where the entire contents (up to 800 mcg) of the teriparatide 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.

Shelf-Life

Not more than 24 months.

Storage And Handling Instructions

ZOTIDE cartridge should be stored at 2–8ºC and should not be frozen.

Packaging Information

ZOTIDE is supplied in a cartridge containing 3 ml of clear colourless solution for injection.

USE ONLY WITH THE ZOTIDE DELIVERY DEVICE-PEN AND ZOTIDE PEN NEEDLES.

USE ZOTIDE CARTRIDGE UP TO 28 DAYS, INCLUDING THE FIRST INJECTION. AFTER 28 DAYS, THROW AWAY THE CARTRIDGE EVEN IF IT IS NOT COMPLETELY EMPTY.

References

1.    Bernabei R, et al. Screening, diagnosis and treatment of osteoporosis: a brief review. Clin Cases Miner Bone Metab. 2014 Sep;11(3):201-7

2.    Cosman F. et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014; 25(10): 2359–2381.

3.    IOF factsheet 2014. Available online: https://www.iofbonehealth.org/sites/default/files/media/PDFs/Fact%20Sheets/2014-factsheet-osteoporosis-A4.pdf Accessed on 26th Aug 2019

4.    IOF facts-statistics 2017. Available online: https://www.iofbonehealth.org/facts-statistics Accessed on 26th Aug 2019

5.    Khadilkar AV, Mandlik RM. Epidemiology and treatment of osteoporosis in women: an Indian perspective. Int J Womens Health. 2015; 7: 841–850.

6.    Madhuri V, Reddy MR. Osteoporosis in Postmenopausal Indian Women – A Case Control Study. Journal of The Indian Academy of Geriatrics, 2010; 6: 14-17

7.    Michael R, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165(15):1762-1768

8.    Pavone V, Testa G, et al. Pharmacological Therapy of Osteoporosis: A Systematic Current Review of Literature.Front Pharmacol. 2017 Nov 7;8:803. doi: 10.3389/fphar.2017.00803. eCollection 2017.

9.    Lombardi G, et al. The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics.J Endocrinol Invest. 2011 Jul;34(7):18-22.

10. Barbara C Silva, John P Bilezikian. Parathyroid hormone: anabolic and catabolic actions on the skeleton. CurrOpinPharmacol. 2015 Jun; 22: 41–50.

11. Kenneth ES Poole and Jonathan Reeve. Parathyroid hormone - a bone anabolic and catabolic agent. Current opinion in pharmacology 2005, 5: 612-617.

12. Thomas C, et al. Parathyroid Disorders. Am Fam Physician. 2013 Aug 15;88(4):249-257.

13. Bodenner D, et al. Teriparatide in the management of osteoporosis. Clinical Interventions in Aging 2007:2(4) 499–507

14. Zotide Prescribing Information (February 2019). Cipla 

15. Kleerekoper M, et al. Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone StrengthJ Bone Joint Surg Am. 2014 Jun 4;96(11): e90

16. Langdahi B, et al. Reduction in Fracture Rate and Back Pain and Increased Quality of Life in Postmenopausal Women Treated with Teriparatide: 18-Month Data from the European Forsteo Observational Study (EFOS)Calcif Tissue Int. 2009; 85:484–493.