teriparatide: prescribing information – dosing, contraindications, interactions, side effects

FORSTEO is indicated in adults.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture (see section 5.1). In postmenopausal women, a significant reduction in the incidence of vertebral and non- vertebral fractures but not hip fractures has been demonstrated.

Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture (see section 5.1).

Posology

The recommended dose of FORSTEO is 20 micrograms administered once daily.

The maximum total duration of treatment with FORSTEO should be 24 months (see section 4.4). The 24-month course of FORSTEO should not be repeated over a patient’s lifetime.

Patients should receive supplemental calcium and vitamin D supplements if dietary intake is inadequate.

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

Special populations

Patients with renal impairment
FORSTEO must not be used in patients with severe renal impairment (see section 4.3.). In patients with moderate renal impairment, FORSTEO should be used with caution. No special caution is required for patients with mild renal impairment.

Patients with hepatic impairment
No data are available in patients with impaired hepatic function (see section 5.3). Therefore, FORSTEO should be used with caution.

Paediatric population and young adults with open epiphyses
The safety and efficacy of FORSTEO in children and adolescents less than 18 years has not been established. FORSTEO should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.

Elderly patients
Dosage adjustment based on age is not required (see section 5.2).

Method of administration

FORSTEO should be administered once daily by subcutaneous injection in the thigh or abdomen.

Patients must be trained to use the proper injection techniques (see section 6.6). A user manual is also available to instruct patients on the correct use of the pen.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Pregnancy and breast-feeding (see sections 4.4 and 4.6)
• Pre-existing hypercalcaemia
• Severe renal impairment
• Metabolic bone diseases (including hyperparathyroidism and Paget’s disease of the bone) other than primary osteoporosis or glucorticoid-induced osteoporosis.
• 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.

Summary of the safety profile

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

Tabulated list of adverse reactions

Of patients in the teriparatide trials, 82.8 % of the FORSTEO patients and 84.5 % of the placebo patients reported at least 1 adverse event.

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 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).

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, hyperuricemia
Rare: Hypercalcaemia greater than 3.25 mmol/L
Psychiatric disorders
Common: Depression
Nervous system disorders
Common: Dizziness, headache, sciatica, syncope

Ear and labyrinth disorders
Common: Vertigo
Cardiac disorders
Common: Palpitations
Uncommon: Tachycardia
Vascular disorders
Common: Hypotension
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea
Uncommon: Emphysema
Gastrointestinal disorders
Common: Nausea, vomiting, hiatus hernia, gastroesophageal reflux disease
Uncommon: Haemorrhoids
Skin and subcutaneous tissue disorders
Common: Sweating increased
Musculoskeletal and connective tissue disorders
Very common: Pain in limb
Common: Muscle cramps
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, pruritis 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
*Serious cases of back cramp or pain have been reported within minutes of the injection.

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.

FORSTEO increases serum uric acid concentrations. In clinical trials, 2.8 % of FORSTEO patients had serum uric acid concentrations above the upper limit of normal compared with 0.7 % of placebo patients. However, the hyperuricemia 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 FORSTEO. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Serum and urine calcium

In normocalcaemic 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 blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent FORSTEO injection. Routine calcium monitoring during therapy is not required.

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

Urolithiasis

FORSTEO has not been studied in patients with active urolithiasis. FORSTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

Orthostatic hypotension

In short-term clinical studies with FORSTEO, isolated episodes of transient orthostatic hypotension were observed. 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, was relieved by placing subjects in a reclining position, and did not preclude continued treatment.

Renal impairment

Caution should be exercised in patients with moderate renal impairment.

Younger adult population

Experience in the younger adult population, including premenopausal women, is limited (see section 5.1). Treatment should only be initiated if the benefit clearly outweighs risks in this population.

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

Duration of treatment

Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide (see section 5.3). Until further clinical data become available, the recommended treatment time of 24 months should not be exceeded.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium- free’.

In a study of 15 healthy subjects administered digoxin daily to steady state, a single FORSTEO dose did not alter the cardiac effect of digoxin. However, sporadic case reports have suggested that hypercalcaemia may predispose patients to digitalis toxicity. Because FORSTEO transiently increases serum calcium, FORSTEO should be used with caution in patients taking digitalis.

FORSTEO has been evaluated in pharmacodynamic interaction studies with hydrochlorothiazide. No clinically significant interactions were noted.

Co-administration of raloxifene or hormone replacement therapy with FORSTEO did not alter the effects of FORSTEO on serum or urine calcium or on clinical adverse events.

Women of childbearing potential / Contraception in females

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

Pregnancy

FORSTEO is contraindicated for use during pregnancy (see section 4.3).

Breast-feeding

FORSTEO is contraindicated for use during breast-feeding. It is not known whether teriparatide is excreted in human milk.

Fertility

Studies in rabbits have shown reproductive toxicity (see section 5.3). The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown.

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

Signs and symptoms

FORSTEO has been administered in single doses of up to 100 micrograms and in repeated doses of up to 60 micrograms/day for 6 weeks.

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

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.

Overdose management

There is no specific antidote for FORSTEO. Treatment of suspected overdose should include transitory discontinuation of FORSTEO, monitoring of serum calcium, and implementation of appropriate supportive measures, such as hydration.

5.
PHARMACOLOGICAL PROPERTIES

Pharmaco-therapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code:
H05 AA02.

Mechanism of action

Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. FORSTEO (rhPTH(1-34)) 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

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

Clinical efficacy

Risk Factors
Independent risk factors, for example, low BMD, age, the existence of previous fracture, family history of hip fractures, high bone turnover and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment.

Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk

for fracture (e.g., low bone density [e.g., T score ≤−2], sustained high dose glucocorticoid therapy [e.g., ≥7.5 mg/day for at least 6 months], high underlying disease activity, low sex steroid levels).

Postmenopausal osteoporosis
The pivotal study included 1637 postmenopausal women (mean age 69.5 years). At baseline, ninety percent of the patients had one or more vertebral fractures, and on average, vertebral BMD was 0.82 g/cm2 (equivalent to a T-score = - 2.6). All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with FORSTEO demonstrate statistically significant fracture reduction (Table 1). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months.

Table 1

Fracture Incidence in Postmenopausal Women:

Placebo
(N = 544) (%)
FORSTEO
(N = 541) (%)
Relative risk
(95% CI) vs. placebo
New vertebral fracture (≥1) a

Distribution

The volume of distribution is approximately 1.7 L/kg. The half-life of FORSTEO is approximately 1 hour when administered subcutaneously, which reflects the time required for absorption from the injection site.

Biostransformation

No metabolism or excretion studies have been performed with FORSTEO but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.

Elimination

FORSTEO is eliminated through hepatic and extra-hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men).

Elderly

No differences in FORSTEO pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.

Teriparatide SUN is indicated in adults.
Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture (see section 5.1). In postmenopausal women, a significant reduction in the incidence of vertebral and non- vertebral fractures but not hip fractures has been demonstrated.

Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture (see section 5.1).

Posology

The recommended dose of teriparatide is 20 micrograms administered once daily.

The maximum total duration of treatment with teriparatide should be 24 months (see section 4.4). The 24-month course of teriparatide should not be repeated over a patient’s lifetime.

Patients should receive supplemental calcium and vitamin D supplements if dietary intake is inadequate.

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

Special populations

Elderly patients
Dose adjustment based on age is not required (see section 5.2).

Renal impairment
Teriparatide must not be used in patients with severe renal impairment (see section 4.3). In patients with moderate renal impairment, teriparatide should be used with caution. No special caution is required for patients with mild renal impairment.

Hepatic impairment
No data are available in patients with impaired hepatic function (see section 5.3). Therefore, teriparatide should be used with caution.

Paediatric population and young adults with open epiphyses
The safety and efficacy of teriparatide in children and adolescents less than 18 years has not been established. Teriparatide SUN should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.

Method of administration

Teriparatide SUN should be administered once daily by subcutaneous injection in the thigh or abdomen.

Patients must be trained to use the proper injection techniques (see section 6.6). Please also refer to the pen user manual for instructions on the correct use of the pen at the end of the package leaflet.

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• pregnancy and breast-feeding (see sections 4.4 and 4.6)
• pre-existing hypercalcaemia
• severe renal impairment
• metabolic bone diseases (including hyperparathyroidism and Paget’s disease of the bone) other than primary osteoporosis or glucorticoid-induced osteoporosis.
• 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.

Summary of the safety profile

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

Tabulated list of adverse reactions

Of patients in the teriparatide trials, 82.8 % of the teriparatide patients and 84.5 % of the placebo patients reported at least 1 adverse event.

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 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).

Table 1. Adverse reaction

MedDRA system organ class
Adverse reaction
Frequency
Blood and lymphatic system disorders
Anaemia
Common
Immune system disorder
Anaphylaxis
Rare
Metabolism and nutrition disorders
Hypercholesterolaemia
Common
Hypercalcaemia greater than

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product should be clearly recorded.

Serum and urine calcium

In normocalcaemic 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 blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required.

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

Urolithiasis
Teriparatide has not been studied in patients with active urolithiasis. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

Orthostatic hypotension

In short-term clinical trials with teriparatide, isolated episodes of transient orthostatic hypotension were observed. 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, was relieved by placing subjects in a reclining position, and did not preclude continued treatment.

Renal impairment

Caution should be exercised in patients with moderate renal impairment.

Younger adult population

Experience in the younger adult population, including premenopausal women, is limited (see section 5.1). Treatment should only be initiated if the benefit clearly outweighs risks in this population.

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

Duration of treatment

Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide (see section 5.3). Until further clinical data become available, the recommended treatment time of 24 months should not be exceeded.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say ‘sodium- free’.

In a study of 15 healthy subjects administered digoxin daily to steady state, a single teriparatide dose did not alter the cardiac effect of digoxin. 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.

Teriparatide has been evaluated in pharmacodynamic interaction studies with hydrochlorothiazide. No clinically significant interactions were noted.

Co-administration of raloxifene or hormone replacement therapy with teriparatide did not alter the effects of teriparatide on serum or urine calcium or on clinical adverse events.

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.

Pregnancy

Teriparatide SUN is contraindicated for use during pregnancy (see section 4.3).

Breast-feeding

Teriparatide SUN is contraindicated for use during breast-feeding. It is not known whether teriparatide is excreted in human milk.

Fertility

Studies in rabbits have shown reproductive toxicity (see section 5.3). The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown.

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

Signs and symptoms

Teriparatide has been administered in single doses of up to 100 micrograms and in repeated doses of up to 60 micrograms/day for 6 weeks.

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

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.

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmaco-therapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code:H05AA02.

Mechanism of action

Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Teriparatide (rhPTH(1-34)) 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.

Clinical efficacy

Risk factors
Independent risk factors, for example, low BMD, age, the existence of previous fracture, family history of hip fractures, high bone turnover and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment.

Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk for fracture (e.g., low bone density [e.g., T score ≤−2], sustained high dose glucocorticoid therapy [e.g., ≥7.5 mg/day for at least 6 months], high underlying disease activity, low sex steroid levels).

Postmenopausal osteoporosis
The pivotal study included 1637 postmenopausal women (mean age 69.5 years). At baseline, ninety percent of the patients had one or more vertebral fractures, and on average, vertebral BMD was 0.82 g/cm2 (equivalent to a T-score = - 2.6). All patients were offered 1 000 mg calcium per day and at least 400 IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with teriparatide demonstrate statistically significant fracture reduction (Table 1). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months.

Table 2 Fracture incidence in postmenopausal women

Placebo
(N = 544) (%)
Teriparatide
(N = 541) (%)
Relative risk
(95% CI) vs. placebo
New vertebral fracture (≥1) a

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.

Biostransformation

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

Elimination

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

Elderly

No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.