Sondelbay

Solution for injection. Colourless, clear solution.
Each dose contains 20 micrograms of teriparatide* in 80 microliters.
One pre-filled pen of 2.4 mL contains 600 micrograms of teriparatide. Each milliliter of the solution for injection contains 250 micrograms of teriparatide.
*Teriparatide, rhPTH (1-34), produced in Escherichia coli, using recombinant DNA technology, is identical to the 34N-terminal amino acid sequence of endogenous human parathyroid hormone.
Exipients/Inactive Ingredients:
Glacial acetic acid, Sodium acetate (anhydrous), Mannitol, Metacresol, Hydrochloric acid (for pH adjustment), Sodium hydroxide (for pH adjustment), Water for injections.

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues. ATC code: H05AA02.
Pharmacology: Pharmacodynamics: Sondelbay is a biosimilar medicinal product.
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 turn over 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). Post menopausal osteoporosis: The pivotal trial 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. (See Table 1.)

Click on icon to see table/diagram/image

After 19 months (median) treatment, (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 trial. The primary objective of the trial 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 trial, 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 from18 to 24 months was 1.4%, 1.2%, and 1.6% at the lumbar spine, total hip and femoral neck, respectively.
A 24-month, randomised, double-blind, comparator-controlled phase 4 trial 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 trial. 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% CI)=0.44 (0.29-0.68), P<0.0001. The cumulative incidence of pooled clinical fractures (clinical vertebral and nonvertebral 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.
Maleosteoporosis: 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 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 trial (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 trial 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, 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 214patients in the teriparatide group (7.5%) (p=0.84).
In premenopausal women, the increase in BMD from baseline to 18 month end point 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). Dose 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 or mice administered teriparatide at daily doses of 30 to 1,000 μg/kg. However, fetal resorption and reduced litter size occurred in pregnant rabbits administered daily doses of 3 to 100 μg/kg.
The embryo toxicity 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).

Teriparatide (Sondelbay) is indicated in adults.
Treatment of osteoporosis in post menopausal women and in men at increased risk of fracture. 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.

Posology: The recommended dose of Sondelbay is 20 micrograms administered once daily.
The maximum total duration of treatment with Sondelbay should be 24 months. The 24-month course of Sondelbay 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 Sondelbay therapy, patients may be continued on other osteoporosis therapies.
Special populations: Elderly: Dose adjustment based on age is not required.
Renal impairment: Sondelbay must not be used in patients with severe renal impairment. In patients with moderate renal impairment, Sondelbay 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. Therefore, Sondelbay 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. Sondelbay should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.
Method of administration: Sondelbay should be administered once daily by subcutaneous injection in the thigh or abdomen.
Patients must be trained to use the proper injection techniques. For instructions of the medicinal product before administration (see Special precautions for disposal and other handling under Cautions for Usage). A user manual is also available to instruct patients on the correct use of the pen.

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 micrograms) 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.
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 skeletal malignancies or bone metastases should be excluded from treatment with teriparatide.

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 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. Sondelbay 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 (>18 to 29 years), including premenopausal women, is limited. 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, Sondelbay should be discontinued.
Duration of treatment: Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide. Until further clinical data become available, the recommended treatment time of 24 months should not be exceeded.
Excipient: This medicinal product contains less than 1 mmol sodium (23 mg) per dose 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, Sondelbay should be discontinued.
Pregnancy: Sondelbay is contraindicated for use during pregnancy.
Breast-feeding: Sondelbay 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. 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, for another teriparatide product antibodies that cross-reacted with that teriparatide product were detected in 2.8% of women. 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.

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: Handling: Sondelbay is supplied in a pre-filled pen. Each pen should be used by only one patient. A new, sterile needle must be used for every injection. No needles are supplied with the product. The pen can be used with pen needles (31G or 32G; 4 mm, 5 mm or 8 mm).
Sondelbay should not be used if the solution is cloudy, coloured or contains particles.
Sondelbay pen should be returned to the refrigerator (2°C-8°C) immediately after use. Recap the pen when not in use to protect the cartridge from physical damage and light.
Do not use Sondelbay if it is, or has been, frozen. Do not transfer the medicine into a syringe.
Do not store the pre-filled pen with the needle attached.
Date of the first injection should be written on the outer carton of Sondelbay (see the provided space: date of first use). Refer to instructions on how to use the pen under Patient Counselling Information.
Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after first opening of the medicinal product, see Shelf life as follows.
Shelf life: 2 years.
After first opening: Chemical, physical and microbiological in-use stability has been demonstrated for 28 days at 2-8°C.
Once opened, the product may be stored for a maximum of 28 days at 2-8°C (refrigerated condition) temperature. Other in-use storage times and conditions are the responsibility of the user.
The medicinal product can be stored at temperature conditions up to 25°C for a maximum of 3 days when refrigeration is not available, after which it should be returned to the refrigerator and used within 28 days of the first injection. The Sondelbay pen should be discarded, if it has been kept out of refrigerator up to 25°C for more than 3 days.

Always use this medicine exactly as your doctor has told you to. Check with your doctor or pharmacist if you are not sure.
The recommended dose is 20 micrograms (in 80 microliters) given once daily by injection under the skin (subcutaneous injection) in the thigh or abdomen. To help you remember to use your medicine, inject it at about the same time each day.
Inject Sondelbay each day for as long as your doctor prescribes it for you. The total duration of treatment with Sondelbay should not exceed 24 months. You should not receive more than one treatment course of 24 months over your lifetime.
Read the instructions for use, on how to use the Sondelbay pen.
Injection needles are not included with the pen. Use with pen needles (31G or 32G; 4 mm, 5 mm or 8 mm).
You should use your Sondelbay injection shortly after you take the pen out of the refrigerator. Put the pen back into the refrigerator immediately after you have used it. Use a new injection needle for each injection and dispose of it after each use. Never store your pen with the needle attached. Never share your Sondelbay pen with others.
Your doctor may advise you to use Sondelbay with calcium and vitamin D. Your doctor will tell you how much you should take each day. Sondelbay can be given with or without food.
If you use more Sondelbay than you should: If, by mistake, you have used more Sondelbay than you should, contact your doctor or pharmacist. The effects of overdose that might be expected include nausea, vomiting, dizziness, and headache.
If you forget or cannot use Sondelbay at your usual time, use it as soon as possible on that day. Do not use a double dose to make up for a forgotten dose. Do not use more than one injection in the same day. Do not try to make up for a missed dose.
If you stop using Sondelbay: If you are considering stopping Sondelbay treatment, discuss this with your doctor. Your doctor will advise you and decide how long you should be treated with Sondelbay.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Agents Affecting Bone Metabolism

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

Rx