BONTEO 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 BONTEO is 20 micrograms administered once daily.
The maximum total duration of treatment with BONTEO should be 24 months (see section 4.4). The 24-month course of BONTEO 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 BONTEO therapy, patients may be continued on other osteoporosis therapies.
Special populations
Patients with renal impairment
BONTEO must not be used in patients with severe renal impairment (see section 4.3). In patients with moderate renal impairment, BONTEO 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, BONTEO should be used with caution.
Paediatric population and young adults with open epiphyses
The safety and efficacy of BONTEO in children and adolescents less than 18 years has not been established. BONTEO 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
BONTEO 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 hypercalcemia • 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 skeletal malignancies or bone metastases should be excluded from treatment with teriparatide

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 BONTEO injection. Routine calcium monitoring during therapy is not required.
BONTEO 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
BONTEO has not been studied in patients with active urolithiasis. BONTEO 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 BONTEO, 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 BONTEO. If pregnancy occurs, BONTEO 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.

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 BONTEO transiently increases serum calcium, BONTEO 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 BONTEO 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 BONTEO. If pregnancy occurs, BONTEO should be discontinued.
Pregnancy
BONTEO is contraindicated for use during pregnancy (see section 4.3).
Pregnancy category: C
Breast-feeding
BONTEO 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.

BONTEO 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.

Summary of the safety profile
The most commonly reported adverse reactions in patients treated with BONTEO 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 summarized 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).

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.
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. BONTEO should not be used in paediatric patients (less than 18 years), or young adults with
open epiphyses.
Special populations
Patients with renal impairment
BONTEO must not be used in patients with severe renal impairment (see section 4.3). In patients with
moderate renal impairment, BONTEO 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, BONTEO
should be used with caution.
Elderly patients
Dosage adjustment based on age is not required (see section 5.2).
To report any side effect(s):

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 BONTEO. Treatment of suspected overdose should include transitory
discontinuation of BONTEO, monitoring of serum calcium, and implementation of appropriate supportive
measures, such as hydration.
 

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. BONTEO (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 BONTEO depend upon
the pattern of systemic exposure. Once-daily administration of BONTEO 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 1,637 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.

After 19 months (median) treatment, bone mineral density (BMD) had increased in the lumbar spine and
total hip, respectively, by 9 % and 4 % compared with placebo (p < 0.001).
Post-treatment management: Following treatment with teriparatide, 1,262 postmenopausal women from
the pivotal trial enrolled in a post-treatment follow-up study. The primary objective of the study was to
collect safety data of teriparatide. During this observational period, other osteoporosis treatments were
allowed and additional assessment of vertebral fractures was performed.
During a median of 18 months following discontinuation of teriparatide, there was a 41 % reduction (p =
0.004) compared with placebo in the number of patients with a minimum of one new vertebral fracture.
In an open-label study, 503 postmenopausal women with severe osteoporosis and a fragility fracture
within the previous 3 years (83 % had received previous osteoporosis therapy) were treated with
teriparatide for up to 24 months. At 24 months, the mean increase from baseline in lumbar spine, total
hip and femoral neck BMD was 10.5 %, 2.6 %, and 3.9 % respectively. The mean increase in BMD from 18
to 24 months was 1.4 %, 1.2 %, and 1.6 % at the lumbar spine, total hip and femoral neck, respectively.
A 24-month, randomized, double-blind, comparator-controlled Phase 4 study included 1,360
postmenopausal women with established osteoporosis. 680 subjects were randomised to teriparatide and
680 subjects were randomised to oral risedronate 35 mg/week. At baseline, the women had a mean age
of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9 % of patients had received previous
bisphosphonate therapy and 18.8 % took concomitant glucocorticoids during the study. 1,013 (74.5 %)
patients completed the 24-month follow-up. The mean (median) cumulative dose of glucocorticoid was
474.3 (66.2) mg in the teriparatide arm and 898.0 (100.0) mg in the risedronate arm. The mean (median)
vitamin D intake for the teriparatide arm was 1433 IU/day (1400 IU/day) and for the risedronate arm was
1191 IU/day (900 IU/day). For those subjects who had baseline and follow-up spine radiographs, the
incidence of new vertebral fractures was 28/516 (5.4 %) in BONTEO- and 64/533 (12.0 %) in risedronatetreated patients, relative risk (95 % CI) = 0.44 (0.29-0.68), P < 0.0001. The cumulative incidence of pooled
clinical fractures (clinical vertebral and non-vertebral fractures) was 4.8 % in teriparatide and 9.8 % in
risedronate-treated patients, hazard ratio (95 % CI) = 0.48 (0.32-0.74), P=0.0009.
Male osteoporosis
437 patients (mean age 58.7 years) were enrolled in a clinical trial for men with hypogonadal (defined as
low-morning free testosterone or an elevated FSH or LH) or idiopathic osteoporosis. Baseline spinal and
femoral neck bone mineral density mean T-scores were -2.2 and -2.1, respectively. At baseline, 35 % of
patients had a vertebral fracture and 59 % had a non-vertebral fracture.
All patients were offered 1,000 mg calcium per day and at least 400 IU vitamin D per day. Lumbar spine
BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbar spine and
total hip by 5 % and 1 %, respectively, compared with placebo. However, no significant effect on fracture
rates was demonstrated.
Glucocorticoid-induced osteoporosis
The efficacy of teriparatide in men and women (N =428) receiving sustained systemic glucocorticoid
therapy (equivalent to 5 mg or greater of prednisone for at least 3 months) was demonstrated in the 18-
month primary phase of a 36-month, randomised, double-blind, comparator-controlled study
(alendronate 10 mg/day). Twenty-eight percent of patients had one or more radiographic vertebral
fractures at baseline. All patients were offered 1,000 mg calcium per day and 800 IU vitamin D per day.
This study included postmenopausal women (N =277), premenopausal women (N =67), and men (N =83).
At baseline, the postmenopausal women had a mean age of 61 years, mean lumbar spine BMD T-score of
-2.7, median prednisone equivalent dose of 7.5 mg/day, and 34 % had one or more radiographic vertebral
fractures; premenopausal women had a mean age of 37 years, mean lumbar spine BMD T-score of -2.5,
median prednisone equivalent dose of 10 mg/day, and 9 % had one or more radiographic vertebral
fractures; and men had a mean age of 57 years, mean lumbar spine BMD T-score of -2.2, median
prednisone equivalent dose of 10 mg/day, and 24 % had one or more radiographic vertebral fractures.
Sixty-nine percent of patients completed the 18-month primary phase. At the 18-month endpoint,
BONTEO significantly increased lumbar spine BMD (7.2 %) compared with alendronate (3.4 %) (p<0.001).
BONTEO increased BMD at the total hip (3.6 %) compared with alendronate (2.2 %) (p<0.01), as well as at
the femoral neck (3.7 %) compared with alendronate (2.1 %) (p<0.05). In patients treated with
teriparatide, lumbar spine, total hip and femoral neck BMD increased between 18 and 24 months by an
additional 1.7 %, 0.9 %, and 0.4 %, respectively.
At 36 months, analysis of spinal X-rays from 169 alendronate patients and 173 teriparatide patients
showed that 13 patients in the alendronate group (7.7 %) had experienced a new vertebral fracture
compared with 3 patients in the BONTEO group (1.7 %) (p=0.01). In addition, 15 of 214 patients in the
alendronate group (7.0 %) had experienced a non-vertebral fracture compared with 16 of 214 patients in
the teriparatide group (7.5 %) (p=0.84).
In premenopausal women, the increase in BMD from baseline to 18-month endpoint was significantly
greater in the BONTEO group compared with the alendronate group at the lumbar spine (4.2 % versus
-1.9 %; p<0.001) and total hip (3.8 % versus 0.9 %; p =0.005). However, no significant effect on fracture
rates was demonstrated.
 

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.
Biotransformation
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.
 

Teriparatide was not genotoxic in a standard battery of tests. It produced no teratogenic effects in rats,
mice or rabbits. There were no important effects observed in pregnant rats or mice administered
teriparatide at daily doses of 30 to 1,000 µg/kg. However, foetal resorption and reduced litter size
occurred in pregnant rabbits administered daily doses of 3 to 100 µg/kg. The embryotoxicity observed in
rabbits may be related to their much greater sensitivity to the effects of PTH on blood-ionised calcium
compared with rodents.
Rats treated with near-lifetime daily injections had dose-dependent exaggerated bone formation and
increased incidence of osteosarcoma most probably due to an epigenetic mechanism. Teriparatide did not
increase the incidence of any other type of neoplasia in rats. Due to the differences in bone physiology in
rats and humans, the clinical relevance of these findings is probably minor. No bone tumours were
observed in ovariectomised monkeys treated for 18 months or during a 3-year follow-up period after
treatment cessation. In addition, no osteosarcomas have been observed in clinical trials or during the
post-treatment follow-up study.
Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to the
principal cleavage system (Kupffer cells) and consequently clearance of PTH(1-84).
 

Glacial acetic acid
Sodium acetate
Mannitol
Metacresol
Water for injection
 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
 

24 months

BONTEO should be stored in a refrigerator (2°C to 8°C) at all times. You can use BONTEO for up to 28 days
after the first injection, as long as the pen is stored in a refrigerator (2°C to 8°C).
Recap the delivery device when not in use to protect the cartridge from physical damage and light
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and pen after EXP. The expiry
date refers to the last day of that month.
Do not freeze BONTEO. Avoid placing the pens close to the ice compartment of the refrigerator to prevent
freezing. Do not use BONTEO if it is, or has been, frozen.
 

BONTEO is a colourless and clear solution. It is supplied in a cartridge contained in a pre-filled disposable
pen. Each pen contains 2.4 mL of solution enough for 28 doses. The pens are available in cartons
containing one pen.
 

Each pen should be properly disposed of after 28 days, even if it is not completely empty.
BONTEO contains a clear and colourless solution. Do not use BONTEO if solid particles appear or if the
solution is cloudy or coloured.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use, these measures will help to protect the environment.