NAME OF THE DRUG

PROTOS(r) strontium ranelate 2g

DESCRIPTION

Description of substance and solubility: Strontium ranelate is a yellowish-white non- hygroscopic powder. It crystallises as a nonahydrate form but one water molecule is particularly labile and this leads to a compound containing either 8 or 9 water molecules per strontium ranelate molecule. Strontium ranelate is slightly soluble in purified water (3.7mg/mL at saturation point) and practically insoluble in organic solvents (eg, methanol).

Excipients:

Aspartame (E951, a source of phenylalanine), maltodextrin, mannitol.

Chemical name: strontium ranelate CAS Registry Number: 135459-90-4 Molecular formula: C12H6N2O8SSr2

Chemical structure:

PHARMACOLOGY

Strontium ranelate has a dual effect on bone metabolism. In vitro it increases bone formation by increasing osteoblast precursor replication and collagen synthesis, and reduces bone resorption by altering osteoclast ultrastructure and decreasing resorbing activity in bone cell culture. The activity of strontium ranelate on both long bones and vertebral bodies was studied in various animal models. Strontium ranelate generally increased bone formation and decreased bone resorption and improved bone biomechanical properties such as bone strength. In bone tissue, strontium is adsorbed onto the crystal surface and substitutes for calcium in the apatite crystal of the newly formed bone, up to a ratio of 1 strontium atom to 10 calcium atoms. Strontium ranelate does not modify the crystal characteristics. In animals, strontium was progressively eliminated from the bone tissue after treatment withdrawal. In phase III studies, as compared to placebo, biochemical markers of bone formation (bone- specific alkaline phosphatase) increased and those of bone resorption (serum C-telopeptide and urinary N-telopeptide cross links) decreased from the third month of treatment up to 3 years. These results confirm the dual mode of action of strontium ranelate on bone cells. In relation to the pharmacological effects of strontium ranelate, slight decreases in calcium and

PROTOS(r) 2g - Data Sheet 2 (12) PTH serum levels, increases in blood phosphorus and in total alkaline phosphatase levels were observed, with no clinical consequences. In human biopsies, the new bone formed with PROTOS treatment is normal (i.e., lamellar) and of good quality with normal mineralisation; in particular, no osteomalacia was observed.

Pharmacokinetics and Metabolism

Strontium ranelate is made up of two atoms of stable strontium and one molecule of ranelic acid, the organic part permitting the best compromise in terms of molecular weight, pharmacokinetics and acceptability of the molecule. The pharmacokinetics of strontium and ranelic acid have been assessed in healthy young men and healthy postmenopausal women, as well as during long-term exposure in postmenopausal osteoporotic women including elderly women. Due to its high polarity, the absorption, distribution and binding to plasma proteins of ranelic acid are low. There is no accumulation of ranelic acid and no evidence of metabolism in animals and humans. Absorbed ranelic acid is rapidly eliminated unchanged via the kidneys.

Absorption

The absolute bioavailability of strontium is 20-25% after an oral dose of 2g strontium ranelate. Steady state is reached after two weeks of treatment. Intake of strontium ranelate with calcium or food reduces the bioavailability of strontium (see Drug Interactions). Oral supplementation with vitamin D has no effect on strontium exposure.

Distribution

Strontium has a volume of distribution of about 1L/kg. The binding of strontium to human plasma proteins is low (25%) and strontium has a high affinity for bone tissue. There is no accumulation of strontium in non-calcified tissues.

Biotransformation

As a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit cytochrome P450 enzymes.

Elimination

The elimination of strontium is time and dose independent. The effective half-life of strontium is about 60 hours. Strontium excretion occurs via the kidneys and the gastrointestinal tract. Its plasma clearance is about 12mL/min and its renal clearance about 7mL/min.

Special Populations

In elderly and very elderly patients, no dosage adjustment is required. In patients with severe renal impairment, in the absence of specific clinical data, PROTOS is contraindicated. In patients with mild to moderate renal impairment, no dosage adjustment is required. Although strontium plasma levels tend to increase in these patients, the safety profile of PROTOS in phase III studies was similar regardless of whether the patients had a creatinine clearance below or above 30mL/min at inclusion.

Preclinical Safety Data

Chronic oral administration of strontium ranelate at high doses in rodents induced bone and tooth abnormalities, including spontaneous fractures, joined vertebrae and delayed mineralisation. These effects were observed at >= 600mg/kg/day in mice and >= 625mg/kg/day in rats (where 77mg/kg/day and 200mg/kg/day is the minimum effective dose that increases bone volume in rats and mice respectively) with bone strontium levels ca 4%. Complete mineralisation of bone tissue occurred after cessation of treatment. Osteodystrophy was also

PROTOS(r) 2g - Data Sheet 3 (12) observed in mice at very high doses i.e. 7500mg/kg/day. (The therapeutic dose of strontium ranelate in humans is 33.3mg/kg/day). Urinary bladder calculi associated with hyperplasia have been observed in one species (mice), and not in other species (rats or monkeys).

CLINICAL TRIALS

Treatment of Postmenopausal Osteoporosis

At menopause, acceleration of bone turnover leads to a decrease in bone mass and bone mineral density (BMD), leading to bone fragility. In some women, this results in postmenopausal osteoporosis. The clinical consequence of osteoporosis is a high risk of fracture. The risk of fracture increases with the number of risk factors. These include early menopause, personal history of fracture, family history of osteoporosis, low body weight, smoking, and factors that may favour falls. Osteoporosis Treatment In postmenopausal women with osteoporosis, PROTOS reduces the incidence of fractures (both vertebral and non-vertebral), and increases bone mass and BMD. The anti-fracture studies program of PROTOS was made up of two international randomised placebo-controlled phase III studies: the Spinal Osteoporosis Therapeutic Intervention (SOTI) study and the Treatment of Peripheral Osteoporosis (TROPOS) study. In addition to their treatment (2g/day strontium ranelate or placebo), the patients received calcium and vitamin D supplements throughout both studies. The following clinical trial results for SOTI and TROPOS are based on three years. The SOTI study involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture) and a mean age of 70 years. The primary efficacy endpoint of this study was the reduction over time in the incidence of a new vertebral fracture in osteoporotic postmenopausal women. The study compared the efficacy of strontium ranelate 2g/day with placebo. Patients included in the study had mean menopause duration of 22+-9 years, and had a mean lumbar BMD T-score of -3.6+-1.3 (T-scores were calculated according to the reference population used in the study, Slosman D.O 1994). 83% of patients had a lumbar BMD T-score <=-2.5 (Slosman D.O 1994). In patients treated with PROTOS over three years, there was a statistically significant reduction in the risk of experiencing a new vertebral fracture (see Table 1).

PROTOS(r) 2g - Data Sheet 4 (12)

years

The TROPOS study involved 5,091 postmenopausal women with mean menopause duration of 28+-7 years and a mean age of 77 years. Patients had osteoporosis (low femoral neck BMD) and more than half had at least one prevalent osteoporosis-related fracture. The primary efficacy endpoint of this study was the reduction over time in the incidence of an osteoporosis- related peripheral fracture in osteoporotic postmenopausal women. The study compared the efficacy of strontium ranelate 2g/day with placebo. The study population had a mean femoral neck BMD T-score of - 3.1+-0.6 (Slosman D.O 1994), and 89% of patients had a femoral neck BMD T-score <=-2.5 (Slosman D.O 1994). In patients treated with PROTOS over three years, there was a statistically significant reduction in the risk of experiencing a non-vertebral fracture (see Table 2).

(1) Adjustment for covariates (age in classes: <75 and >=75 years, femoral neck BMD, BMI in classes: <= 18, [18-30] and > 30 kg/m2, and country) (2) According to substitution rules for covariates. In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS studies showed that there was a statistically significant reduction in the risk of experiencing both new vertebral and non-vertebral fractures over three years of treatment with PROTOS (see Table 3). The pooled analysis of SOTI and TROPOS also showed a statistically significant reduction in the relative risk of experiencing a new vertebral fracture in patients with osteopenia (defined according to WHO criteria as patients with lumbar and/or femoral neck BMD T-score <=-1SD and both T-scores >-2.5SD) (see Table 3).

PROTOS(r) 2g - Data Sheet 5 (12)

CONTRAINDICATIONS

Known hypersensitivity to strontium ranelate or to any of the excipients Severe renal impairment (see Pharmacokinetics - Special Populations) Current or previous venous thromboembolic events (VTE), including deep vein thrombosis and pulmonary embolism. Temporary or permanent immobilisation (e.g. post-surgical recovery or prolonged bed rest).

PROTOS(r) 2g - Data Sheet 6 (12) History of ischaemic heart disease, peripheral arterial disease or cerebrovascular disease Systolic blood pressure (SBP) greater than or equal to 160 mmHg, or diastolic blood pressure (DBP) greater than or equal to 90 mmHg.

PRECAUTIONS

PROTOS is only intended for use in postmenopausal women. Treatment should only be initiated by a doctor with experience in treating osteoporosis. The decision to prescribe PROTOS should be based on an assessment of the individual patient's overall risks (see CONTRAINDICATIONS and PRECAUTIONS). Patients should be evaluated for cardiovascular risk prior to commencement of PROTOS and during ongoing treatment (see PRECAUTIONS - Cardiac ischaemic events) Calcium and vitamin D deficiencies occur frequently in the elderly, particularly in the institutionalised or those who avoid direct sun exposure. Patients should receive vitamin D and calcium supplements if dietary intake is inadequate.

Venous thromboembolism

In phase III placebo controlled studies, strontium ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism (VTE), including pulmonary embolism (see Adverse Reactions section). The cause of this finding is unknown. PROTOS is contraindicated in patients with a past history of venous thromboembolic events (see CONTRAINDICATIONS) and should be used with caution in patients at risk of VTE. In patients over 80 years at risk of VTE, ongoing treatment with PROTOS should be re- evaluated. In the event of an illness or a condition leading to immobilisation (see CONTRAINDICATIONS), PROTOS should be discontinued as soon as possible and adequate preventive measures taken. Therapy should not be restarted until the event has resolved and the patient is mobile. PROTOS should be stopped if VTE occurs. PROTOS contains aspartame, a source of phenylalanine, which may be harmful for people with phenylketonuria. Treatment with PROTOS should be discontinued in case of allergic reaction to strontium ranelate or to any of the excipients.

Cardiac ischaemic events

In pooled randomised placebo-controlled studies of patients with post-menopausal osteoporosis, a significant increase in myocardial infarction has been observed in PROTOS treated patients compared to placebo (see ADVERSE REACTIONS). Patients should be evaluated for cardiovascular risk prior to commencement of PROTOS and during ongoing treatment. Patients with significant risk factors for cardiovascular events should only be treated with PROTOS after careful consideration (see ADVERSE REACTIONS and CONTRAINDICATIONS). Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or if SBP is greater than or equal to 160 mmHg, or DBP is greater than or equal to 90 mmHg (see CONTRAINDICATIONS).

Hypersensitivity reactions

Cases of life-threatening cutaneous reactions [Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS)] have been reported with the use of PROTOS. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment and usually

around 3-6 weeks for DRESS.

PROTOS(r) 2g - Data Sheet 7 (12) If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) or DRESS [e.g. rash, fever, eosinophilia and systemic involvement (e.g. adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease)] are present, PROTOS treatment should be discontinued immediately. Early diagnosis and immediate discontinuation of the suspected drug is associated with a better prognosis of SJS, TEN or DRESS. In cases of DRESS consider initiation of corticosteroid therapy following discontinuation of PROTOS. Recovery from DRESS could be slow and recurrences have been reported in some cases after discontinuation of corticosteroid therapy. If the patient has developed SJS, TEN or DRESS with the use of PROTOS, PROTOS must not be re-started. A higher incidence (although rare) of hypersensitivity reactions including skin rash, SJS or TEN has been reported in patients of Asian origin (see ADVERSE REACTIONS- Post Marketing Experience).

Carcinogenicity

Strontium ranelate was non-genotoxic in a battery of assays including in vitro bacterial gene mutation (Salmonella typhimurium and E. coli), in vitro mammalian cell gene mutation (Chinese hamster fibroblast cells), in vitro chromosome aberration (human lymphocytes), in vitro unscheduled DNA synthesis in rat hepatocytes, and in vivo bone marrow micronucleus formation in rodents.

Mutagenicity

Long-term studies with strontium ranelate at oral doses (in the diet) up to 1800 mg/kg/day in mice and 625/900 (male/female) mg/kg/day in rats showed no treatment-related increase in the incidence of tumours. These doses resulted in plasma strontium and ranelic acid AUC values approximately 2 and 4-6 times the average clinical value, respectively.

Effects on Fertility

Male and Female fertility in rats were unaffected by strontium ranelate treatment (1000mg/kg/day, with plasma AUC values for strontium similar to the average clinical value).

Use in Pregnancy - Category B3

PROTOS is only intended for use in postmenopausal women. No clinical data on exposed pregnancies are available for strontium ranelate. Animal reproductive studies showed bone abnormalities (eg. bent bones, wavy ribs, arthrogryposis) of the foetus from pregnant rats and rabbits at oral doses >= 500mg/kg/day, which results in plasma AUC values for strontium and ranelic acid lower than or similar to the average clinical value. These effects were reversible eight weeks after cessation of treatment. If women taking PROTOS become pregnant, they should stop taking it immediately.

Use in Lactation

Strontium accumulates in rat milk, giving milk/plasma ratios up to 73 at an oral dose of 750mg/kg/day strontium ranelate. High levels of strontium were detected in the plasma of suckling neonates of lactating rats treated with strontium ranelate. Strontium ranelate treatment of lactating rats delayed incisor eruption of the offspring. PROTOS should not be given to breast-feeding women.

Paediatric Use

Use not recommended, as no data are available in children.

Effects on Ability to Drive and Use Machines

There are no data to suggest that PROTOS affects the ability to drive or use machines.

INTERACTIONS WITH OTHER MEDICINES

PROTOS(r) 2g - Data Sheet 8 (12) Food, milk and derivative products, and medicines containing calcium may reduce the bioavailability of strontium ranelate. Therefore, PROTOS should preferably be taken at least two hours after such products (see Pharmacokinetics). As divalent cations form a complex with oral tetracycline and quinolone antibiotics at the gastro- intestinal level, thus reducing their absorption, simultaneous administration of strontium ranelate with these drugs is not recommended. As a precautionary measure, PROTOS treatment should be suspended during treatment with oral tetracycline or quinolone antibiotics and reintroduced the day following the last antibiotic dose. Strontium ranelate is not metabolised, does not inhibit cytochrome P450 enzymes and has low protein binding. As a consequence, PROTOS is not expected to interact with other medicinal products. No interaction was observed with oral supplementation of vitamin D. There are no clinical data concerning the concomitant medication with one or more bisphosphonates and such concomitant medication is not recommended.

Effects on Laboratory Tests

Strontium interferes with colorimetric methods for the determination of blood and urinary calcium levels. Therefore, in medical practice, inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry methods should be used to ensure an accurate assessment of blood and urinary calcium levels. The combined effects of the atomic weight and increased X-ray absorption of strontium as compared to calcium, lead to an amplification of bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry (DXA). Available data indicate that these factors account for approximately 50% of the measured change in BMD over 3 years of treatment with PROTOS 2g/day. This should be taken into account when interpreting BMD changes during treatment with PROTOS.

DOSAGE AND ADMINISTRATION

Treatment should only be initiated by a doctor with experience in treating osteoporosis (see PRECAUTIONS). The recommended daily dose for the treatment of osteoporosis is one 2g sachet once daily by oral administration (see Clinical Trials section). Due to the nature of this disease, PROTOS is intended for long-term use (see Adverse Reactions section). As with all chronic diseases, the management of osteoporosis should be reviewed on a regular basis and current practice guidelines should be consulted.

Method of Administration

Patients should preferably take PROTOS at bedtime since the absorption of strontium ranelate may be affected by food intake (see Drug Interactions and Pharmacokinetics). PROTOS can be taken on an empty stomach. The granules in the sachets must be taken as a suspension in a glass containing a minimum of 30ml (approximately one third of a standard glass) of water. Although in-use studies have demonstrated that strontium ranelate is stable in suspension for 24 hours after preparation, the suspension should be drunk immediately after preparation.

Use in the Elderly

The efficacy and safety of PROTOS have been established in a broad age range (up to 100 years at inclusion) of postmenopausal women with osteoporosis. No dosage adjustment is required in relation to age, even in the very elderly.

Use in Renal Impairment

No dosage adjustment is required in patients with mild to moderate renal impairment. PROTOS is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS and Pharmacokinetics - Special Populations).

Use in Hepatic Impairment

As strontium ranelate is not metabolised, no dosage adjustment is required in patients with hepatic impairment.

OVERDOSAGE

Good tolerance was shown in a clinical study investigating the repeated administration of 4g strontium ranelate per day over 25 days in healthy postmenopausal women. Single administration of doses up to 11g in healthy young male volunteers did not cause any particular symptoms. Following episodes of overdoses during clinical trials (up to 4g/day for a maximal duration of 147 days), no clinically relevant events were observed. Administration of milk or antacids may be helpful to reduce the absorption of the drug. In the event of substantial overdose, vomiting may be considered to remove unabsorbed drug. Advice on overdose management can be obtained from the national Poisons Information Centre by telephoning 131126.

PROTOS(r) 2g - Data Sheet 12 (12)

PRESENTATION

Granules for oral suspension. PROTOS 2g sachets contain 2g strontium ranelate as a yellow powder. Boxes contain 7 or 28 sachets (paper/polyethylene/aluminium/polyethylene sachets).

STORAGE

Store in a dry place below 30oC. Shelf life: three years in original packaging. 24 hours after suspension in drinking water.

POISONS SCHEDULE

S4. Prescription Medicine.

NAME AND ADDRESS OF THE SPONSOR

SERVIER LABORATORIES (NEW ZEALAND) LTD Level 4, Zurich House 21 Queen Street Auckland Central Auckland 1010

DATE OF PREPARATION

15 May, 2013