Preotact100 micrograms powder and solvent for solution for injection.

Preotact contains parathyroid hormone manufactured using a strain of Escherichia coli modified by recombinant DNA technology.

The medicinal product is supplied in a dual-chamber cartridge.

The first chamber contains 1.61 mg parathyroid hormone.

Each dose of 71.4 microliter contains 100 micrograms parathyroid hormone. Each cartridge contains 14 doses.

The second chamber contains a sterile solvent for reconstitution.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

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

Treatment of osteoporosis in postmenopausal women at high risk of fractures (see section 5.1).

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

The recommended dose is 100 micrograms of parathyroid hormone administered once-daily 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 available with the Preotact pen to instruct patients on the correct use of the pen. The pen is not included in the packs with cartridges.

Patients should receive supplemental 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 density (see section 5.1).

Specific populations

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 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).

Children and adolescents

The safety and efficacy of Preotact in patients under 18 years have not been studied. Preotact should not be used in paediatric patients or young adults.

Elderly

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

Preotact is contraindicated in patients

• with hypersensitivity to parathyroid hormone or to any of the excipients (see section 6.1)

• who have previously received radiation therapy to the skeleton

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

• with metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease of the bone)

• with unexplained elevations of bone-specific alkaline phosphatase

• with severe renal impairment

• with severe hepatic impairment

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 observed during Preotact treatment. Serum calcium concentrations reach a maximum between 6 and 8 hours post dose 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 elevated serum calcium

Patients with persistent elevated serum calcium (above the upper normal level) should be evaluated for underlying disease (e.g. hyperparathyroidism). If no underlying condition is found, the following management procedures should be followed:

• Calcium and vitamin D supplementation should be withdrawn

• The 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

Patients with pre-existing hypercalcemia and/or hypercalciuria

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

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

Caution should be exercised in patients receiving cardiac glucosides (see section 4.5).

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.

Preotact contains metacresol, which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose.

Parathyroid hormone is a natural peptide that is not metabolised by, and does not inhibit hepatic 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.

Combining parathyroid hormone with alendronate use has not been shown to provide any advantage over either form of treatment alone, when the end point of bone mineral density was evaluated. (see section 5.1).

From the knowledge of the mechanism of action, combined use of Preotact and cardiac glucosides may predispose patients to digitalis toxicity if hypercalcemia develops.

There are no data available from the use of parathyroid hormone during pregnancy and lactation. Animal studies of reproductive toxicity are incomplete (see section 5.3).

Parathyroid hormone should not be used during pregnancy or breast-feeding.

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.

The following adverse reaction (ADR) data are based on two placebo-controlled studies involving 2642 postmenopausal osteoporotic women of whom 1341 received parathyroid hormone. Approximately 71.4 % of the patients on parathyroid hormone reported at least one ADR.

Hypercalcemia and/or hypercalciuria reflect the known pharmacodynamic actions of parathyroid hormone in the gastrointestinal tract, the kidney, and the bone. Hypercalcemia was reported in 25.3 % of patients and hypercalciuria in 39.3 % of patients treated with Preotact. 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, 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 undesirable effects by frequency of occurrence: very common (> 1/10); common ( > 1/100 and <1/10); uncommon ( > 1/1000 and <1/100); rare ( > 1/10,000 and <1/1000); and very rare ( <1/10,000), including isolated reports.

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 titer, there was no evidence of hypersensitivity reactions, allergic reactions, effects on bone mineral density response, or effects on serum calcium.

Signs and symptoms

In the Preotact clinical program, accidental overdose was reported for 17 subjects.

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.

Pharmacotherapeutic group: parathyroid hormone, ATC code: H05 AA03.

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 2532 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, and 2 %, respectively, in the 3 groups.

Treatment of osteoporosis with combination and sequential therapy

The PaTH study was a NIH sponsored randomised, placebo-controlled, 2 year, multicenter, double-blind trial of Preotact and alendronate as monotherapy and in combination for the treatment of postmenopausal osteoporosis. Inclusion criterias 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 below –2.5, and 112 (47 %) reported at least one 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 months after Preotact was discontinued), there was a 12.1 % mean increase in dual energy X-ray absorptiometry (DXA) spine BMD for patients who received alendronate for the second year. For the patients who received placebo during the second year, the mean percent increase was 4.1 % compared to baseline, 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 % vs. 1.1 %, p<0.001). The combination was effective regardless of age, baseline rate of bone turnover, or baseline BMD.

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. Intersubject 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 dose of 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 to normal liver plasma flow and is consistent with extensive hepatic metabolism of the active substance. Intersubject variability in systemic clearance is about 15 %.

Elimination

Parathyroid hormone is metabolised in the liver and to a lesser degree in the kidney. Parathyroid hormone is not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken to even smaller fragments during tubular reuptake.

Hepatic impairment

There was a modest increase of about 20 % in the mean baseline corrected exposure (AUC) to parathyroid hormone in a study conducted in 6 men and 6 women with 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 C_max 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 ml/min) 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 30 ml/min) has not been investigated.

Elderly

No differences in Preotact pharmacokinetics were detected with regard to age (range 47-88 years). Dosage adjustment based on age is not required.

Gender

The medicinal product has only been studied in postmenopausal women.

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.

Powder

Mannitol

Citric acid monohydrate

Sodium chloride

Hydrochloric acid, dilute (for pH adjustment)

Sodium hydroxide 1N (for pH adjustment)

Solvent

Metacresol

Water for injections

Not applicable.

Powder: 30 months

Mixed solution: chemical and physical in-use stability has been demonstrated for 28 days at 2-8°C. During the 28-day period the mixed solution can be stored for up to 7 days at temperatures below 25°C.

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

Keep the cartridge in the outer carton in order to protect from light.

Mixed solution: Store in a refrigerator (2-8°C). Do not freeze. Once the cartridge is mixed 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).

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: The glass of the dual-chamber cartridge is made of glass Type I.

Stopper (center and end): The stopper is made of bromobutyl rubber, grey.

Crimp cap (containing a rubber seal): The crimp cap is made of aluminium and the rubber seal is made of bromobutyl rubber.

Each dual-chamber cartridge contains 1.61 mg parathyroid hormone and 1.13 ml solvent (14 doses).

Preotact is available in packs of 2 and 6 cartridges. Not all pack sizes may be marketed.

The Preotact pen and needles are not included.

Preotact is injected using the re-usable pen, Preotact pen. The contents of the dual-chamber cartridge is mixed in the Preotact pen. After mixing the liquid should be clear and colourless.

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

If the mixed solution is cloudy, coloured or contains particles the cartridge should be removed from the Preotact pen and a new cartridge inserted.

Any unused product or waste material should be disposed of in accordance with local requirements.

Nycomed Danmark ApS

Langebjerg 1

DK-4000 Roskilde

Denmark

EU/1/06/339/001-002

24 April 2006