SmPC KAULIV 20mcg / 80mcl solution for injection

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATCcode: H05AA02

Kauliv is a biosimilar medicinal product. Detailed information is available on the website ofthe European Medicines Agency http://www.ema.europa.eu.

Endogenous 84-amino -acid parathyroid hormone (PTH) is the primary regulator of calcium andphosphate metabolism in bone and kidney. Teriparatide (rh PTH (1-34)) is the active fragment (1-34) of endogenous human parathyroid hormone. Physiological actions of PTH include stimulationof bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing theintestinal absorption of calcium and increasing the tubular re-absorption of calcium and excretionof phosphate by the kidney.

Teriparatide is a bone formation agent to treat osteoporosis. The skeletal effects of teriparatidedepend upon the pattern of systemic exposure. Once-daily administration of teriparatide increasesapposition of new bone on trabecular and cortical bone surfaces by preferential stimulation ofosteoblastic activity over osteoclastic activity.

Independent risk factors, for example, low BMD, age, the existence of previous fracture, familyhistory of hip fractures, high bone turnover and low body mass index should be considered in orderto identify women and men at increased risk of osteoporotic fractures who could benefit fromtreatment.

Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high riskfor fracture if they have a prevalent fracture or a combination of risk factors that place them at highrisk 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 was0.82 g/cm2 (equivalent to a T-score = - 2.6). All patients were offered 1 000 mg calcium per dayand at least 400 IU vitamin D per day. Results from up to 24 months (median:19 months)treatment withteriparatide demonstrate statistically significant fracture reduction (Table 2). To prevent one ormore new vertebral fractures, 11 women had to be treated for a median of 19 months.

Table 2. Fracture incidence in postmenopausal women

Placebo Teriparatide Relative risk(N = 544) (%) (N = 541) (%) (95 % CI)

Vs. placebo

New vertebral fracture (≥1)a 0.3514.3 5.0b(0.22, 0.55)

Multiple vertebral fractures (≥1)a 0.234.9 1.1b(0.09, 0.60)

Non-vertebral fragility fracturesc 0.475.5% 2.6%b(0.25, 0.87)

Major non-vertebral fragility fracturesc 0.383.9% 1.5%b(hip, radius, humerus, ribs and pelvis) (0.17, 0.86)

Abbreviations: N = number of patients randomly assigned to each treatment group; CI =confidence interval.a The incidence of vertebral fractures was assessed in 448 placebo and 444 teriparatide patients whohad baseline and follow-up spine radiographs.b p≤0.001 compared with placebo.c A significant reduction in the incidence of hip fractures has not been demonstrated.

p≤0.025 compared with placebo.

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 womenfrom the pivotal trial enrolled in a post-treatment follow-up study. The primary objective of the studywas to collect safety data of teriparatide. During this observational period, other osteoporosistreatments 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 vertebralfracture.

In an open-label study, 503 postmenopausal women with severe osteoporosis and a fragilityfracture within the previous 3 years (83% had received previous osteoporosis therapy) were treatedwith 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 femoralneck, respectively.

A 24-month, randomised, double-blind, comparator-controlled phase 4 study included 1 360postmenopausal women with established osteoporosis. 680 subjects were randomised to teriparatideand 680 subjects were randomised to oral risedronate 35 mg/week. At baseline, the women had amean age of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9% of patients hadreceived previous bisphosphonate therapy and 18.8% took concomitant glucocorticoids during thestudy. 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 armwas 1 433 IU/day (1,400 IU/day) and for the risedronate arm was 1 191 IU/day ( 900 IU/day).

For those subjects who had baseline and follow-up spine radiographs, the incidence of newvertebral 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 incidenceof pooled clinical fractures (clinical vertebral and non-vertebral fractures) was 4.8% in teriparatideand 9.8% in risedronate-treated patients, hazard ratio (95% CI) = 0.48 (0.32-0.74), p = 0.0009.

Male osteoporosis437 patients (mean age 58.7 years) were enrolled in a clinical trial for men with hypogonadal (definedas low morning free testosterone or an elevated FSH or LH) or idiopathic osteoporosis. Baselinespinal and femoral neck BMD mean T-scores were -2.2 and -2.1, respectively. At baseline, 35% ofpatients 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. Lumbarspine BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbarspine and total hip by 5% and 1%, respectively, compared with placebo. However, no significanteffect on fracture rates was demonstrated.

Glucocorticoid-induced osteoporosis

The efficacy of teriparatide in men and women (N=428) receiving sustained systemic glucocorticoidtherapy (equivalent to 5 mg or greater of prednisone for at least 3 months) was demonstrated inthe 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 vertebralfractures at baseline. All patients were offered 1 000 mg calcium per day and 800 IU vitamin Dper day.

This study included postmenopausal women (N=277), premenopausal women (N=67), andmen (N=83). At baseline, the postmenopausal women had a mean age of 61 years, meanlumbar 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 37years, mean lumbar spine BMD T score of −2.5, median prednisone equivalent dose of 10mg/day, and 9% had one or more radiographic vertebral fractures; and men had a mean age of 57years, mean lumbar spine BMD T score of −2.2, median prednisone equivalent dose of 10mg/day, and 24% had one or more radiographic vertebral fractures.

Sixty-nine percent of patients completed the 18-month primary phase. At the 18 monthendpoint, teriparatide significantly increased lumbar spine BMD (7.2%) compared withalendronate (3.4%) (p<0.001). Teriparatide increased BMD at the total hip (3.6%) comparedwith alendronate (2.2%) (p<0.01), as well as at the femoral neck (3.7%) compared withalendronate (2.1%) (p<0.05). In patients treated with teriparatide, lumbar spine, total hip andfemoral neck BMD increased between 18 and 24 months by an additional 1.7%, 0.9%, and0.4%, respectively.

At 36 months, analysis of spinal X-rays from 169 alendronate patients and 173 teriparatide patientsshowed that 13 patients in the alendronate group (7.7%) had experienced a new vertebral fracturecompared with 3 patients in the teriparatide group (1.7%) (p=0.01). In addition, 15 of 214 patientsin 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 endpoint wassignificantly greater in the teriparatide group compared with the alendronate group at the lumbarspine (4.2% versus−1.9%; p<0.001) and total hip (3.8% versus 0.9%; p=0.005). However, no significant effecton fracture rates was demonstrated.