Terrosa

Teriparatide.

Each dose of 80 microliters contains 20 micrograms of teriparatide*.
One cartridge of 2.4 mL of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per mL).
Colourless, clear solution for injection with a pH of 3.8 - 4.5.
*Teriparatide, rhPTH(1-34), produced in P. fluorescens, using recombinant DNA technology, is identical to the 34 N-terminal amino acid sequence of endogenous human parathyroid hormone.
Excipients/Inactive Ingredients: Glacial acetic acid, Mannitol, Metacresol, Sodium acetate trihydrate, Hydrochloric acid 10% solution (if needed for pH adjustment), Sodium hydroxide 10% solution (if needed for pH adjustment), Water for injections.

Pharmaco-therapeutic group: Calcium homeostasis, parathyroid hormones and analogues. ATC code: H05 AA02.
Pharmacology: Pharmacodynamics: TERROSA 20 μg/80 μL solution for injection is a biosimilar medicinal product.
Mechanism of action: Endogenous 84-amino-acid parathyroid hormone (PTH) is a 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 and safety: 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 not 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 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 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. (See Table 1.)

Click on icon to see table/diagram/image

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 teriparatide- and 64/533 (12.0%) in risedronate-treated patients, relative risk (95% Cl) = 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% Cl) = 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 1000 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 has 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 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 1000 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, 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 months endpoint, teriparatide significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). Teriparatide 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 teriparatide 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 months endpoint was significantly greater in the teriparatide 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.
Pharmacokinetics: 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.
Toxicology: Preclinical safety data: 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 and mice administered teriparatide at daily doses of 30 to 1000 μg/kg. However, foetal resorption and reduced litter size occurred in pregnant rabbits 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-life time 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).

TERROSA 20 μg/80 μL solution for injection is indicated in adults.
Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture (see Pharmacology: Pharmacodynamics under Actions). In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures have been demonstrated.
Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture (see Pharmacology: Pharmacodynamics under Actions).

Posology: The recommended dose of teriparatide is 20 micrograms administered once daily.
Patients should receive supplemental calcium and vitamin D supplements if dietary intake is inadequate.
The maximum total duration of treatment with teriparatide should be 24 months (see Precautions).
The 24-month course of teriparatide should not be repeated over a patient's lifetime.
Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies.
Special populations: Renal impairment: Teriparatide must not be used in patients with severe renal impairment (see Contraindications). In patients with moderate renal impairment, Teriparatide 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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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 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 Pharmacology: Pharmacokinetics under Actions)
Method of administration: TERROSA 20 μg/80 μL solution for injection should be administered once daily by subcutaneous injection in the thigh or abdomen.
It should be administered exclusively with the Terrosa Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions which are provided with the pen. The pen and injection needles are not included with TERROSA 20 μg/80 μL solution for injection. However, for the treatment initiation a cartridge and pen pack should be used containing one carton of TERROSA 20 μg/80 μL solution for injection cartridge and one carton of Terrosa Pen.
TERROSA 20 μg/80 μL solution for injection must not be used with any other pen.
Patients must be trained to use the proper injection techniques (see Special precautions for disposal <and other handling> under Cautions for Usage). An instruction for use which is included in the carton of the delivery system is also available to instruct patients on the correct use of the pen.
The date of first injection should also be written on the outer carton of TERROSA 20 μg/80 μL solution for injection (see the provided space on the box: {First use}).

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 when 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Pregnancy and breast-feeding (see Precautions and Use in Pregnancy & Lactation).
Pre-existing hypercalcaemia.
Severe renal impairment.
Metabolic bone diseases (including hyperparathyroidism and Paget's diseases 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.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Adverse Reactions for how to report adverse reactions.

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 studies 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 Pharmacology: Pharmacodynamics under Actions). Treatment should only be initiated if the benefit clearly outweighs risks in this population.
Duration of treatment: Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide (see Pharmacology: Toxicology: Preclinical safety data under Actions). Until further clinical data become available, the recommended treatment time of 24 months should not be exceeded.
Documentation: Batch (Lot) number of each cartridge and the date of its first injection should be recorded by the patient on a calendar.
Excipient: This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially "sodium-free".
Effects on ability to drive and use machines: Teriparatide 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.

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 is contraindicated for use during use of pregnancy (see Contraindications).
Breast-feeding: Teriparatide 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 Pharmacology: Toxicology: Preclinical safety data under Actions). The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown.

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 as follows.
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). (See Table 2.)

Click on icon to see table/diagram/image

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 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 teriparatide. Generally, antibodies were first detected following 12 months of treatment of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions, allergic reactions, effect 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.

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.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal <and other handling>: Terrosa 20 μg/80 μL solution for injection is supplied in a cartridge. Terrosa 20 μg/80 μL solution for injection cartridges are to be used in Terrosa Pen reusable, multidose pen device exclusively and must not be used with any other pen. No needles are supplied with this medicinal product.
Each cartridge and pen should be used by only one patient. The pen can be used with compatible pen needles. These are listed in the instructed for use for the pen. A new, sterile pen needle must be used for every injection.
The expiry date on the cartridge label must always be checked before inserting the cartridge into Terrosa Pen. To avoid medication errors make sure that the date when starting to use a new cartridge is at least 28 days before its expiry date.
Before using the pen device for the first time, the patient should read and understand the instructions on how to use the pen which are provided with the pen.
After each injection, the pen should be returned to the refrigerator. After the first use, the cartridge should not be removed from the pen during the 28 days of usage.
Terrosa 20 μg/80 μL solution for injection must not be transferred to a syringe.
Empty cartridges must not be refilled.
Terrosa 20 μg/80 μL solution for injection should not be used if the solution is cloudy, coloured or contains visible particles.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator (2°C-8°C). After insertion of the cartridge into the pen, the combined pen and cartridge should be returned to the refrigerator immediately after use.
Do not freeze. Keep the cartridge in the outer carton in order to protect from light.
Do not store the injection device with the needle attached. Do not remove the cartridge from the pen after first use.
For storage conditions after first opening of the medicinal product, see Shelf life as follows.
Shelf life: 2 years.
Chemical in-use stability has been demonstrated for 28 days at 2-8°C.
From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days within its shelf life at 2°C to 8°C.
Other in-use storage times and conditions are the responsibility of the user.

Agents Affecting Bone Metabolism

H05AA02 - teriparatide ; Belongs to the class of parathyroid hormones and analogues. Used in the management of calcium homeostasis.

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