Preotact - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Preotact 100 micrograms powder and solvent for solution for injection in a pre-filled pen.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen contains 1.61 mg parathyroid hormone corresponding to 14 doses.

After reconstitution, each dose of 71.4 microlitre contains 100 micrograms parathyroid hormone produced in Escherichia coli by recombinant DNA technology

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

White to off-white powder and clear, colourless solvent.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Preotact is indicated for the treatment fractures (see section 5.1).

A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated.

4.2 Posology and method of administr

Posology

The recommended dose is 100 micrograms of parathyroid hormone administered once-daily

calcium and vitamin D if dietary intake is inadequate.

Data support continuous treatment with Preotact for up to 24 months (see section 4.4).

Following treatment with Preotact patients can be treated with a bisphosphonate to further increase bone mineral y (see section 5.1).

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justment is necessary in patients with mild to moderate renal impairment (creatinine e 30 to 80 ml/min). There is no data available in patients with severe renal impairment. Preotact should therefore not be used in patients with severe renal impairment (see section 4.3).

Hepatic impairment

No dose adjustment is needed for patients with mild or moderate hepatic impairment (total score of 7 to 9 on the Child-Pugh scale). There is no data available in patients with severe hepatic impairment. Preotact should therefore not be used in patients with severe hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of Preotact in patients under 18 years have not been studied. There is no relevant use of Preotact in paediatric patients for the treatment of osteoporosis at high risk of fractures

Elderly

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

Method of administration

The dose is administered as a subcutaneous injection into the abdomen.

Patients must be trained to use the proper injection techniques (see section 6.6). A user manual is included in the box to instruct patients on the correct use of the pen.

Precautions to be taken before handling or administering the medicinal product

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Preotact is contraindicated in patients

• • with hypersensitivity to parathyroid hormone or to any of the excipients
• • who are receiving or who has previously received radiation therapy to th

with skeletal malignancies or bone metastases.

with pre-existing hypercalcemia and other disturbances in the phosphocalcic metabolism

with metabolic bone diseases other than primary oste and Paget’s disease of the bone)

with unexplained elevations of bone-specific alkaline with severe renal impairment with severe hepatic impairment

4.4 Special warnings and precautions for use

Monitoring of patients during treatment

Patients initiated on Preotact therapy should be monitored at months 1, 3 and 6 for elevated levels of serum and/or urinary calcium. Monitoring beyond 6 months is not recommended for patients whose total serum calcium is within the normal limits at 6 months.

Elevated serum calcium was observ     ring Preotact treatment. Serum calcium concentration­s reach

a maximum between 6 and 8 hours      ose and normally return to baseline by 20 to 24 hours after

each administration of parathyroid hormone. Therefore if any blood samples are taken from a patient for monitoring of calcium levels, this should be done at least 20 hours after the most recent injection.

Management of elevate m calcium

Patients with persistent elevated serum calcium (above the upper normal level) should be evaluated for underlying dis e.g. hyperparathyro­idism). If no underlying condition is found, the following ures should be followed: and vitamin D supplementation should be withdrawn

frequency of Preotact dosing should be changed to 100 micrograms every other day If elevated levels continue, Preotact therapy should be stopped and the patient monitored until the abnormal values have reverted to normal

Caution should be exercised in

Patients with pre-existing hypercalciuria

Preotact has been studied in patients with pre-existing hypercalciuria. In these patients, Preotact treatment was more likely to exacerbate their underlying hypercalciuria.

Patients with urolithiasis

Preotact has not been studied in patients with active urolithiasis. Preotact should be used with caution in patients with active or previous urolithiasis.

Patients receiving cardiac glucosides

Caution should be exercised in patients receiving cardiac glucosides due to the risk of digitalis toxicity if hypercalcemia develops (see section 4.5).

Duration of treatment

Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of Preotact (see section 5.3). The occurrence of osteosarcoma only occurred at doses that produced systemic exposures > 27-times higher than that observed in humans at the 100 micrograms dose. Until further clinical data becomes available the recommended treatment time of 24 months should not be exceeded.

4.5 Interaction with other medicinal products and other forms of interaction

Parathyroid hormone is a natural peptide that is not metabolised by, and does not in microsomal drug-metabolising enzymes (e.g. cytochrome P450 isoenzymes). Furthermore, parathyroid hormone is not protein bound and has a low volume of distribution. Consequently, no interaction with other medicinal products would be anticipated and no specific drug-drug interactions studies were performed. No potential for drug interactions was identified in the clinical program.

From the knowledge of the mechanism of action, combined use of Preotac

may predispose patients to digitalis toxicity if hypercalcemia develops (see section 4.4).

4.6 Fertility, pregnancy and lactation

There are no data available from the use of parathyroid hormone men of childbearing potential, during pregnancy and breast feeding. Animal studies of reproductive toxicity are incomplete (see section 5.3).

Parathyroid hormone should not be used in women of childbearing potential, during pregnancy or breast-feeding.

4.7 Effects on ability to drive and u

No studies on the effects on the ability to drive and use machines have been performed. As some episodes of dizziness have been described in patients treated with Preotact, patients should refrain from driving or using machines until symptoms have subsided.

4.8 Undesirable effects

The following adverse reaction (ADR) data are based on two placebo-controlled studies involving 2,642 postmeno­pausal osteoporotic women of whom 1,341 received parathyroid hormone.

Approxi 71.4% of the patients on parathyroid hormone reported at least one ADR.

ia and/or hypercalciuria reflect the known pharmacodynamic actions of parathyroid n the gastrointestinal tract, the kidney, and the bone. Hypercalcemia was reported in 25.3% ients and hypercalciuria in 39.3% of patients treated with Preotact. Hypercalcemia was transient was reported most frequently in the first 3 months of treatment. It was managed during the clinical programme by monitoring laboratory values and the use of a pre-specified management algorithm (see sections 4.3, 4.4, and 5.1).

The only other very commonly reported ADR was nausea.

The table below gives an overview of the ADRs where the incidence is at least 0.5% higher in the parathyroid hormone group compared to placebo. The following categories are used to rank the adverse reactions by frequency of occurrence: 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); and very rare (<1/10,000), including isolated reports.

Nervous system disorders

Common

Headache

Dizziness

Uncommon

Dysgeusia

Parosmia

Cardiac disorders

Common

Palpitations _______

Gastrointestinal disorders Very common Nausea Common Vomiting Constipation Dyspepsia Diarrhoea Uncommon Abdomina l pain

Musculo

Common Muscle c

n extremity pain

Renal and urinary disorders

Very common

Hypercalciuria

Common

Urine calcium/creatinine ratio increased

Urine calcium increased

General disorders and administration site conditions

Common Injection site erythema Fatigue Asthenia Uncommon Injection site irritation

2.6 1.8 1.2 0.9

Preotact increases serum uric acid concentrations. For all subjects who received parathyroid hormone 100 micrograms blood uric acid increase was reported for 8 subjects (0.6%) and hyperuricemia was reported for 5 subjects (0.4%). Although gout, arthralgia and nephrolithiasis were reported as ADRs, the relationship to elevations in uric acid due to Preotact administration has not been fully established.

Antibodies to parathyroid hormone

In a large phase III clinical study, antibodies to parathyroid hormone were detected in 3% of women receiving Preotact compared to 0.2% of women receiving placebo. In these women with a positive titre, there was no evidence of hypersensitivity reactions, allergic reactions, effects on bone mineral density response, or effects on serum calcium.

4.9 Overdose

Signs and symptoms

In the Preotact clinical program, accidental overdose has been reported.

Preotact has been administered in single doses up to 5 micrograms/kg and in repeated doses of up to 3 micrograms/kg/day for 3 days and up to 2.5 microgram­s/kg/day for 7 days. The effects of overdose that might be expected include delayed hypercalcemia, nausea, vomiting, dizziness and headache.

Overdose management

There is no specific antidote for Preotact. Treatment of suspected overdose should include temporary discontinuation of Preotact, monitoring of serum calcium, and implementation of appropriate, supportive measures, such as hydration. Due to the relatively short duration of the pharmacological activity of Preotact further measures should not be necessary.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium homeostatis, parathyroid hormones and analogues, ATC code: H05AA03.

Mechanism of action

Preotact contains recombinant human parathyroid hormone which is identical to the full-length native 84-amino acid polypeptide.

Physiological actions of parathyroid hormone include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney.

Pharmacodynamic effects

The skeletal effects of parathyroid hormone depend upon the pattern of systemic exposure. Transient elevations in parathyroid hormone levels after subcutaneous injection of Preotact stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

Effects on serum calcium concentrations

Parathyroid hormone is the principal regulator of serum calcium homeostasis. In response to subcutaneous doses of Preotact (100 micrograms parathyroid hormone), serum total calcium levels increase gradually and reach peak concentration (mean increase in 129 patients, 0.15 mmol/l) at approximately 6 to 8 hours after dosing. In general, serum calcium levels return to baseline levels 24 hours after dosing.

Based on two placebo-controlled studies involving 2642 postmenopausal osteoporotic women, hypercalcemia was reported in 25.3% of patients treated with Preotact compared to 4.3% of placebo-treated patients. The hypercalcemia was transient and was reported most frequently in the first 3 months of treatment. It was managed during the clinical programme by monitoring laboratory values and the use of a pre-specified management algorithm (see sections 4.3 and 4.4).

Clinical efficacy

Effect on fracture incidence

The pivotal study was an 18-month double-blind, placebo-controlled, phase III study (TOP) of the effect of Preotact on fracture incidence in women with postmenopausal osteoporosis.

A total of 2532 patients (1286 Preotact and 1246 placebo), aged 45–94 years (8.1% 45–54 years and 11.4% > 75 years), were randomised to receive 100 micrograms/day or placebo with daily calcium (700 mg) and vitamin D (400 IU) supplementation.

Overall, approximately 19% of the subjects in each treatment group had at least 1 prevalent vertebral fracture at baseline. The mean baseline lumbar T score was approximately –3.0 in each treatment group.

Of the 2,532 randomised intention-to-treat (ITT) patients, a total of 59 patients experienced at least one new vertebral fracture, placebo: 42 (3.37%) – Preotact: 17 (1.32%), p=0.001. Patients in the Preotact treatment group had a 61% relative risk reduction of a new vertebral fracture at month 18 compared to the patients in the placebo group.

To prevent one or more new vertebral fractures, 48 women had to be treated for a median of 18 months for the total population. For patients with pre-existing fractures, number needed to treat (NNT) is 21 patients.

There was no significant difference between the treatment groups in the incidence of any non-vertebral clinical fracture: 5.52% for Preotact vs. 5.86% for placebo.

The most relevant fracture reduction was observed among patients at high risk of fractures such as patients with previous fractures and in patients with a lumbar spine T-score of < - 3.

Relatively few patients less than 5 years postmenopausal and 45–54 years of age were enrolled in the phase III study (2–3%). The results for these subjects were not different from the results in the study as a whole.

Effect on bone mineral density (BMD)

In the pivotal study, Preotact increased BMD in the lumbar spine after 18 months treatment by 6.5% compared with –0.3% for placebo (p<0.001). Significant increases in hip BMD (total, femoral neck, trochanter) were observed at study endpoint; 1.0, 1.8 and 1.0%, respectively, for Preotact versus –1.1, –0.7 and –0.6% for placebo (p<0.001).

Continued treatment for up to 24 months in an open-label extension of this study resulted in a continued increase in BMD. The increase from baseline in lumbar spine and femoral neck BMD was 6.8% and 2.2%, respectively in patients treated with Preotact.

The effects of Preotact on bone architecture were evaluated using quantitative computed tomography (QCT) and peripheral QCT. Volumetric trabecular BMD at the lumbar spine increased by 38% over baseline at 18 months. Similarly, volumetric trabecular BMD at the total hip increased by 4.7%. Similar increases occurred at the femoral neck, trochanter, and intertrochanter. Treatment with Preotact reduced volumetric cortical bone BMD (measured at the distal radius and mid-shaft tibia), while periosteal circumference or indices of cortical bone strength were maintained.

In the 24-month alendronate combination therapy study (PaTH), the effects of Preotact on bone architecture were also evaluated using QCT. Volumetric trabecular BMD at the lumbar spine increased by 26, 13, and 11% (Preotact, Preotact and alendronate and alendronate, respectively) over baseline at 12 months. Similarly, volumetric trabecular BMD at the total hip increased by 9, 6, an 2%, respectively, in the 3 groups.

Treatment of osteoporosis with combination and sequential therapy

The PaTH study was a National Institute of Health (NIH) sponsored randomised, placeb year, multicenter, double-blind trial of Preotact and alendronate as monotherapy and in c for the treatment of postmenopausal osteoporosis. Inclusion criteria were; women between 55 and 85 years of age with BMD T-scores below –2.5 or below –2 and at least one additional risk factor for fracture. All women were given calcium (400–500 mg) and vitamin D (400 IU) supplements.

A total of 238 postmenopausal women, were randomly assigned to one of the following treatment groups; Preotact (100 micrograms parathyroid hormone), alendronate (10 mg), or the combination of both, and followed for 12 months. In the second year of the study women in the original Preotact group were randomly assigned to receive either alendronate or matching placebo, and women in the other two groups received alendronate.

At baseline a total of 165 women (69%) had a T-score fracture after menopause.

One year of therapy, showed the following results: the increases in lumbar spine BMD above baseline were similar in the Preotact and combination-therapy groups (6.3 and 6.1%, respectively), but were somewhat smaller in the alendronate group (4.6%). Increases in BMD at the total hip were 0.3, 1.9, and 3.0% for the 3 groups, respectively.

At the end of year 2 (12 mont fter Preotact was discontinued), there was a 12.1% mean increase in dual energy X-ray absorptio      (DXA) spine BMD for patients who received alendronate for the

second year. For the patient o received placebo during the second year, the mean percent increase was 4.1% compared to bas line, but had decreased slightly compared to the end of 12 months of Preotact treatment. For the mean change in hip BMD, there was a 4.5% increase from baseline with one year of alendronate compared to a 0.1% decrease after one year of placebo.

Preotact in combination with hormone replacement therapy (HRT) in 180 postmenopausal women has been shown to significantly increase lumbar spine BMD at 12 months compared with HRT alone (7.1 1%, p<0.001). The combination was effective regardless of age, baseline rate of bone , or baseline BMD.

5.2 Pharmacokinetic properties

Absorption

Subcutaneous administration of 100 micrograms of parathyroid hormone into the abdomen produces a rapid increase in plasma parathyroid hormone levels and achieves a peak at 1 to 2 hours after dosing. The average half-life is of about 1.5 hours. The absolute bioavailability of 100 micrograms of parathyroid hormone after subcutaneous administration in the abdomen is 55%.

Distribution

The volume of distribution at steady-state following intravenous administration is approximately 5.4 l.

Interindividual variability in the volume of distribution of parathyroid hormone is about 40%.

Biotransformation

Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminius are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of parathyroid hormone activity. Under normal physiologic conditions, full-length parathyroid hormone (1–84) constitutes only 5–30% of the circulating forms of the molecule, while 70–95% is present as carboxy-terminal fragments. Following a subcutaneous dos Preotact, C-terminal fragments make up about 60–90% of the circulating forms of the molecule. Systemic clearance of parathyroid hormone (45.3 l/hour) following an intravenous dose is close t normal liver plasma flow and is consistent with extensive hepatic metabolism of the acti     bstance.

Interindividual variability in systemic clearance is about 15%.

Elimination

Parathyroid hormone is metabolised in the liver and to a lesser degree in the hormone is not excreted from the body in its intact form. Circulating carbox filtered by the kidney, but are subsequently broken to even

Hepatic impairment

There was a modest increase of about 20% in the mean baseline ted exposure (AUC) to parathyroid hormone in a study conducted in 6 men and 6 wome moderate hepatic impairment as compared with a matched group of 12 subjects with normal hepatic function.

No studies have been conducted in patients with severe hepatic impairment.

Renal impairment

The overall exposure and Cmax of parathyroid hormone were slightly increased (22% and 56%, respectively) in a group of 8 male and 8 female subjects with mild-to-moderate renal impairment (creatinine clearances of 30 to 80 m ) compared with a matched group of 16 subjects with normal renal function.

The pharmacokinetics of parathyroid hormone in patients with severe renal impairment (creatinine clearance of less than      /min) has not been investigated.

Elderly

No differences in Preotact pharmacokinetics were detected with regard to age (range 47–88 years).

Dosa            t based on age is not required.

icinal product has only been studied in postmenopausal wo­men.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, mutagenicity, toxicity to fertility and general reproduction, and local tolerance.

In monkeys receiving daily subcutaneous doses for 6 months, there was an increased occurrence of renal tubular mineralization at exposure levels below clinical exposure levels.

Rats treated with near life-time daily injections had dose-dependent exaggerated bone formation and an increased incidence of bone tumours, including osteosarcoma, most probably due to an epigenetic mechanism. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is probably minor. No osteosarcomas have been observed in clinical trials.

There are no studies of foetal, developmental, perinatal or postnatal toxicity. It is unknown whether recombinant human parathyroid hormone is excreted in the milk of lactating animals.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder

Mannitol

Citric acid monohydrate

Sodium chloride

Hydrochloric acid, dilute (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Solvent

Metacresol

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

Reconstituted solution: chemical and physical in-use stability has been demonstrated for 28 days at 28°C. During the 28-day period the reconstituted solution can be stored for up to 7 days at temperatures below 25°C.

• 64 S • I f f

6.4 Special precautions for storage

Do not store above 25°C. Do not freeze.

Keep the product protected from light.

Reconstituted solution: Store in a refrigerator (2–8°C). Do not freeze. Once the product is reconstituted it can be stored outside the refrigerator at temperatures below 25°C for up to 7 days during the 28 day use period (see section 6.3).

6.5 Nature and contents of container

The medicinal product is supplied in a pre-filled pen containing a dual-chamber cartridge.

The container closure system is comprised of a dual-chamber cartridge, a center stopper, a crimp cap (containing a rubber seal) sealing the first chamber containing lyophilised powder and an end stopper sealing the second chamber containing the solvent for mixing.

Cartridge: Glass Type I.

Stopper (center and end): Bromobutyl rubber, grey.

Crimp cap (containing a rubber seal): Aluminium.The rubber seal is made of bromobutyl rubber.

Each cartridge inside the prefilled pen contains 1.61 mg parathyroid hormone and 1.13 ml solvent (14 doses).

Preotact is available in packs of 2 pre-filled pens.

6.6 Special precautions for disposal and other handling

Preotact is injected using a pre-filled pen. Each pen should be used by only one patient. A new sterile needle must be used for every injection. The pen can be used with standard injection pen needles. The content of the cartridge is reconstituted in the pen. After reconstitution the liquid should be clear and

colourless.

DO NOT SHAKE; shaking may cause denaturation of the active substance.

Preotact should not be used if the reconstituted solution is cloudy, coloured or contains p Please see how to use the pen in the Instructions for use manual.

Any unused product or waste material should be disposed of in accordance wit

7. MARKETING AUTHORISATION HOLDER

NPS Pharma Holdings Limited Grand Canal House

• 1 Grand Canal Street Upper

Dublin 4

Ireland

8

EU/1/06/339/003