KAULIV 20mcg / 80mcl injectible solution medication leaflet

Kauliv 20 micrograms/80 microliters solution for injection

Each dose of 80 microliters contains 20 micrograms of teriparatide*.

Each cartridge of 3 mL of solution contains 750 micrograms of teriparatide (corresponding to250 micrograms per mL).

*Teriparatide, rhPTH (1-34), produced in E. coli, using recombinant DNA technology, is identical tothe 34-N-terminal amino acid sequence of endogenous human parathyroid hormone.

For the full list of excipients, see section 6.1.

Solution for injection.

Colourless, clear solution for injection.

Kauliv is indicated in adults.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture (seesection 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 andmen at increased risk for fracture (see section 5.1).

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

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

The maximum total duration of treatment with teriparatide should be 24 months (see section 4.4). The24-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.

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

Teriparatide must not be used in patients with severe renal impairment (see section 4.3). In patientswith moderate renal impairment, teriparatide should be used with caution. No special caution isrequired for patients with mild renal 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 have not beenestablished. Teriparatide should not be used in paediatric patients (less than 18 years), or young adultswith open epiphyses.

Kauliv 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). For instructions of themedicinal product before administration (see section 6.6). Instructions for use which is included in thecarton of the pen are 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) otherthan 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 withteriparatide.

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

Serum and urine calcium

In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have beenobserved following teriparatide injection. Serum calcium concentrations reach a maximum between4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, ifblood samples for serum calcium measurements are taken, this should be done at least 16 hours afterthe most recent teriparatide injection. Routine calcium monitoring during therapy is not required.

Teriparatide may cause small increases in urinary calcium excretion, but the incidence ofhypercalciuria 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 withcaution in patients with active or recent urolithiasis because of the potential to exacerbate thiscondition.

In short-term clinical trials with teriparatide, isolated episodes of transient orthostatic hypotensionwere observed. Typically, an event began within 4 hours of dosing and spontaneously resolved withina few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within thefirst several doses, was relieved by placing subjects in a reclining position, and did not precludecontinued treatment.

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 section5.1). 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 ofteriparatide. If pregnancy occurs, teriparatide should be discontinued.

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

This medicinal product 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 teriparatide dosedid not alter the cardiac effect of digoxin. However, sporadic case reports have suggested thathypercalcaemia may predispose patients to digitalis toxicity. Because teriparatide transiently increasesserum calcium, teriparatide should be used with caution in patients taking digitalis.

Teriparatide has been evaluated in pharmacodynamic interaction studies with hydrochlorothiazide. Noclinically significant interactions were noted.

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

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

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

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

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

Kauliv has no or negligible influence on the ability to drive and use machines. Transient, orthostatichypotension or dizziness was observed in some patients. These patients should refrain from driving orthe use of machines until symptoms have subsided.

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

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

The adver se 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), and rare (≥1/10 000 to<1/1 000).

Table 1. Adverse reactions

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Common Anaemia

Immune system disorders Rare Anaphylaxis

Common Hypercholesterolaemia

Uncommon Hypercalcaemia greater than

Metabolism and nutrition disorders 2.76 mmol/L, hyperuricaemia

Rare Hypercalcaemia greater than3.25 mmol/L

Psychiatric disorders Common Depression

Nervous system disorders Common Dizziness, headache, sciatica, syncope

Ear and labyrinth disorders Common Vertigo

Common Palpitations

Uncommon Tachycardia

Vascular disorders Common Hypotension

Respiratory, thoracic and Common Dyspnoeamediastinal disorders Uncommon Emphysema

Common Nausea, vomiting, hiatus hernia,gastro-oesophageal reflux disease

Uncommon Haemorrhoids

Skin and subcutaneous tissue disorders Common Sweating increased

Very common Pain in limb

Musculoskeletal and connectivetissue disorders Common Muscle cramps

Uncommon Myalgia, arthralgia, back cramp/pain*

Uncommon Urinary incontinence, polyuria,micturition urgency, nephrolithiasis

Rare Renal failure/impairment

Fatigue, chest pain, asthenia,mild and transient injection site events,

Common including pain, swelling, erythema,localised bruising, pruritus andminor bleeding at injection site

General disorders andadministration site condition Uncommon Injection site erythema,injection site reaction

Possible allergic events soon after injection:

Rare acute dyspnoea, oro/facial oedema,generalised urticaria, chest pain,oedema (mainly peripheral)

Weight increased,

Investigations Uncommon cardiac murmur,alkaline phosphatase increased

*Serious cases of back cramp or pain have been reported within minutes of the injection.

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 patientshad serum uric acid concentrations above the upper limit of normal compared with 0.7% of placebopatients. However, the hyperuricaemia did not result in an increase in gout, arthralgia, or urolithiasis.

Anti-drug antibodies if any are likely to be observed in line with other teriparatide containingmedicinal products. There was no evidence of hypersensitivity reactions, allergic reactions, effects onserum calcium, or effects on Bone Mineral Density (BMD) response.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Signs and symptoms

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

The effects of overdose that might be expected include delayed hypercalcaemia and risk of orthostatichypotension. 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 entirecontents (up to 750 micrograms) of a 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 havebeen reported.

Overdose management

There is no specific antidote for teriparatide. Treatment of suspected overdose should includetransitory discontinuation of teriparatide, monitoring of serum calcium, and implementation ofappropriate supportive measures, such as hydration.

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code:

H05AA02

Kauliv is a biosimilar medicinal product. Detailed information is available on the website of the

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 stimulation of boneformation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinalabsorption of calcium and increasing the tubular re-absorption of calcium and excretion of phosphateby the kidney.

Teriparatide is a bone formation agent to treat osteoporosis. The skeletal effects of teriparatide dependupon the pattern of systemic exposure. Once-daily administration of teriparatide increases appositionof new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblasticactivity 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 order toidentify 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 forfracture if they have a prevalent fracture or a combination of risk factors that place them at high riskfor 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, ninetypercent 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 day andat 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 or morenew 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)a14.3 5.0b 0.35(0.22, 0.55)

Multiple vertebral fractures (≥1)a4.9 1.1b 0.23(0.09, 0.60)

Non-vertebral fragility fracturesc5.5% 2.6%b 0.47(0.25, 0.87)

Major non-vertebral fragility fracturesc 0.38(hip, radius, humerus, ribs and pelvis) 3.9% 1.5%b (0.17, 0.86)

Abbreviations: N = number of patients randomly assigned to each treatment group; CI = confidenceinterval.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 fragility fracturewithin the previous 3 years (83% had received previous osteoporosis therapy) were treated withteriparatide for up to 24 months. At 24 months, the mean increase from baseline in lumbar spine, totalhip and femoral neck BMD was 10.5%, 2.6 % and 3.9% respectively. The mean increase in BMDfrom 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, 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 a meanage of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9% of patients had receivedprevious 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 ofglucocorticoid was 474.3 (66.2) mg in the teriparatide arm and 898.0 (100.0) mg in the risedronatearm. The mean (median) vitamin D intake for the teriparatide arm was 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 andfollow-up spine radiographs, the incidence of new vertebral fractures was 28/516 (5.4%) interiparatide- 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 andnon-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 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. Baseline spinaland femoral neck BMD mean T-scores were -2.2 and -2.1, respectively. At baseline, 35% of patientshad 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 in the18-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 D perday.

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 moreradiographic vertebral fractures; premenopausal women had a mean age of 37 years, mean lumbarspine BMD T score of −2.5, median prednisone equivalent dose of 10 mg/day, and 9% had one ormore 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 moreradiographic 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). Inpatients treated with teriparatide, lumbar spine, total hip and femoral neck BMD increased between18 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 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 patients inthe 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 was significantlygreater 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 onfracture rates was demonstrated.

The volume of distribution is approximately 1.7 L/kg. The half-life of teriparatide is approximately1 hour when administered subcutaneously, which reflects the time required for absorption from theinjection site.

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

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

No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to85 years). Dose 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 administeredteriparatide at daily doses of 30 to 1 000 micrograms/kg. However, foetal resorption and reduced littersize occurred in pregnant rabbits administered daily doses of 3 to 100 micrograms/kg. Theembryotoxicity 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 andincreased incidence of osteosarcoma most probably due to an epigenetic mechanism. Teriparatide didnot increase the incidence of any other type of neoplasia in rats. Due to the differences in bonephysiology in rats and humans, the clinical relevance of these findings is probably minor. No bonetumours were observed in ovariectomised monkeys treated for 18 months or during a 3-year follow-upperiod after treatment cessation. In addition, no osteosarcomas have been observed in clinical trials orduring the post treatment follow-up study.

Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to theprincipal cleavage system (Kupffer cells) and consequently clearance of PTH(1-84).

Glacial acetic acid

Mannitol

Metacresol

Anhydrous sodium acetate

Diluted hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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

24 months

Chemical, physical and microbiological in-use stability has been demonstrated for 28 days at 2 - 8°C.

Once opened, the medicinal product may be stored for a maximum of 28 days within its shelf life at2°C to 8°C. After insertion of the cartridge into the pen, the combined pen and cartridge should bereturned to the refrigerator immediately after use. Do not store the pen with the needle attached. Donot remove the cartridge from the pen after first use. The cartridge within the pen can additionally beplaced in the pouch supplied with the pen in order to protect from light.

Other in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C - 8°C).

Do not freeze. Keep the cartridge in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

3 mL cartridge (USP type-1 glass cartridge), with a plunger stopper (bromobutyl) and disc seal(aluminium and rubber liner seals), packed in a plastic tray sealed with lid foil and supplied in acarton.

Each cartridge contains 3 mL solution for injection corresponding to 28 doses of 20 micrograms (per80 microliters).

Kauliv 1 cartridge or 3 cartridges.

Kauliv cartridge and pen pack:1 inner carton of Kauliv cartridge (containing 1 cartridge) and 1 inner carton of Kauliv Pen (containing1 pen).

Not all pack sizes may be marketed.

Handling

Kauliv cartridges should be used exclusively within Kauliv reusable, multidose pen. No needles aresupplied with this medicinal product.

Each cartridge and pen should be used by only one patient. The pen can be used with 32 G 4 mmsingle-use pen needles.

A new, sterile needle must be used for every injection.

The expiry date on the cartridge label must always be checked before inserting the cartridge into

Kauliv pen. To avoid medication errors, make sure that the date when starting to use a new cartridge isat least 28 days before its expiry date.

Before using the pen for the first time, the patient should read and understand the instructions on howto 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 cartridgeshould not be removed from the pen during the 28 days of usage. Do not use Kauliv if it is, or has beenfrozen.

Kauliv must not be transferred to a syringe. Empty cartridges must not be refilled.

Kauliv should not be used if the solution is cloudy, coloured or contains visible particles.

The date of first injection should be written on the outer carton of Kauliv cartridge (see the providedspace on the box: “First use“).

The Kauliv reusable pen features a dose selector with audible clicks and visual indicators to ensurecorrect dose is set for priming (P) and for setting the dose (D).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Strides Pharma (Cyprus) Ltd.

Themistokli Dervi, 3

Julia House, 1st Floor,1066, Nicosia,

Cyprus

EU/1/22/1710/001 [1 cartridge]

EU/1/22/1710/002 [3 cartridges]

EU/1/22/1710/003 [cartridge and pen pack]

Date of first authorisation:

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu