PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 15 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 17

PHARMACEUTICAL INFORMATION 17 CLINICAL TRIALS 18 DETAILED PHARMACOLOGY 20 MICROBIOLOGY 26 TOXICOLOGY 26 REFERENCES 31

PART III: CONSUMER INFORMATION. 32

SOMATULINE(r) AUTOGEL(tm)

lanreotide injection 60mg, 90mg, 120 mg lanreotide (as acetate) /unit (syringe)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Patients who are hypersensitive to somatostatin or related peptides. Patients with complicated, untreated lithiasis of the bile ducts

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Loss of blood glucose control (hypoglycemia in diabetic patients; hyperglycemia ) can occur (see Endocrine and Metabolism section)

• Gall bladder motility may be reduced and lead to gall stone formation (see Hepatic/Biliary/Pancreatic section)

• Drug interaction with cyclosporin (see Drug Interactions section)

Cardiovascular

Lanreotide may lead to a decrease of heart rate without necessarily reaching the threshold of bradycardia in patients without an underlying cardiac problem. In patients suffering from cardiac disorders prior to lanreotide initiation, sinus bradycardia may occur and therefore heart rate should be monitored.

Endocrine and Metabolism

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and its analogues, inhibits the secretion of insulin and glucagon. Hence, patients treated with Somatuline Autogel may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is changed and treatment of diabetic patients should be adjusted accordingly. In insulin-dependent patients, insulin requirements may be reduced. [2.7.2.3.5.2]

Gastrointestinal

The gastrointestinal effects of lanreotide may reduce the intestinal absorption of co-administered drugs. [2.7.2.2.2/2.7.4.5.3]

Hepatic/Biliary/Pancreatic

Lanreotide may reduce gall bladder motility and lead to gall stone formation. Gall bladder ultrasonography is therefore advised at the start of treatment and periodically thereafter. [2.7.2.3.5.2] In hepatic impairment, an increase in Volume of Distribution, Mean Residence Time, AUC and half-life were observed. Clearance was reduced by 30% only in moderate to severe hepatically impaired patients. Due to the wide therapeutic window of lanreotide and the fact that dosage is titrated against reduction in GH and IGF-1, it is not necessary to alter the dose in these circumstances. [2.7.2.2.2.3 / 2.7.2.3.3] (see Action and Clinical Pharmacology section)

Renal

Subjects with severe renal impairment show an approximately 2-fold decrease in total serum clearance of lanreotide, with a consequent increase in half-life and AUC. Due to the wide therapeutic window of lanreotide it is not necessary to alter the dose in these circumstances. [2.7.2.2.2.3 / 2.7.2.3.3] (see Action and Clinical Pharmacology section)

Special Populations

Pregnant Women: [2.7.4.5.4]

There is very limited experience of pregnancy in patients treated with lanreotide, either during clinical trials or from post marketing reports.

Studies in animals showed a transitory growth retardation of offspring prior to weaning. Although no teratogenic effects have been observed in animals, Somatuline Autogel should be administered to pregnant women only if clearly needed. [2.7.4.5.4]

Nursing Women: [2.7.4.5.4]

It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk precaution should be exercised. Somatuline Autogel should be administered to breast-feeding women only if clearly needed.

Pediatrics (< 16 years of age): [-]

There is no experience of the use of the product in children in this indication and therefore the use of Somatuline Autogel in children cannot be advised.

Geriatrics (> 65 years of age): [2.7.2.2.2.3 / 2.7.2.3.3]

Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. Due to the wide therapeutic window of lanreotide, it is not necessary to alter the dose in these circumstances.

(see Action and Clinical Pharmacology section)

Monitoring and Laboratory Tests

Evaluation of GH and IGF-1 levels are useful markers of the disease progression and effectiveness of treatment (See Dosage and Administration section). In patients suffering from cardiac disorders prior to lanreotide initiation, sinus bradycardia may occur and therefore heart rate should be monitored. The principal pharmacodynamic interaction that may occur is the inhibition of glucagon secretion which may lead to the onset of hypoglycemia in treated diabetic patients, notably insulin-dependent patients. Thus, the insulin requirements in insulin-dependent diabetic patients may be reduced. Therefore blood glucose levels should be monitored when lanreotide treatment is initiated or when the dosage is attuned. The treatment of diabetic patients should be adjusted accordingly. Lanreotide may reduce gall bladder motility and lead to gall stone formation. Gall bladder ultrasonography is therefore advised at the start of treatment and periodically thereafter.

DRUG INTERACTIONS

Serious Drug Interactions

• Concomitant administration of lanreotide injection with cyclosporin may decrease blood levels of cyclosporin (see Drug-Drug Interactions section)

Overview

The gastrointestinal effects of Somatuline Autogel may reduce the intestinal absorption of co- administered drugs. No significant interaction was found with vitamin K when administered concomitantly with lanreotide. [2.7.2.2.2 / 2.7.4.5.3] Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins (78% mean serum binding). [2.7.2.2.1.1 / 2.7.4.5.3] (see Extrinsic Factor Pharmacokinetic Studies section) Limited published data indicate that somatostatin analogues might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other medicinal products mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. terfenadine) should therefore be used with caution.

Drug-Drug Interactions

Concomitant administration of lanreotide injection with cyclosporin may decrease blood levels of cyclosporin, hence blood levels of cyclosporin should be monitored. Concomitant administration of lanreotide and bromocriptine increases the availability of bromocriptine. [2.7.2.2.2 / 2.7.4.5.3]

The drugs listed in this section are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Drug-Food Interactions

Interactions with food have not been established. [-]

Drug-Herb Interactions

Interactions with herbal products have not been established. [-]

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established. [-]

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Patients should begin treatment with Somatuline Autogel 90 mg given via deep subcutaneous route, at 4 week intervals for 3 months. After 3 months dosage may be adapted as follows:

• GH >1 to <= 2.5 ng/mL, IGF-1 normal and clinical symptoms controlled: Maintain Somatuline Autogel dosage at 90 mg every 4 weeks

• GH > 2.5 ng/mL, IGF-1 elevated and/or clinical symptoms uncontrolled: Increase Somatuline Autogel dosage to 120 mg every 4 weeks

• GH <= 1 ng/mL, IGF-1 normal and clinical symptoms controlled: Reduce Somatuline Autogel dosage to 60 mg every 4 weeks.

Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in symptoms and/or in GH and /or IGF-1 levels. Due to the wide therapeutic window of lanreotide it is not necessary to alter the dose in hepatic or renal impairment or in the elderly (see WARNINGS and PRECAUTIONS).

Missed Dose

If a dose is missed, the next dose should be administered as soon as possible.

Administration

Somatuline Autogel should be injected via the deep subcutaneous route in the superior external quadrant of the buttock. The skin should not be folded. The needle should be inserted rapidly to its full length, perpendicularly to the skin. The injection site should be alternated. Somatuline Autogel is provided in a pre-filled syringe and is ready for use. Somatuline Autogel is for immediate and single use following first opening.

OVERDOSAGE

If overdose occurs, symptomatic management is indicated. Experience with lanreotide overdose in humans consists of a single case, a 52-year-old acromegalic patient with medical history of diabetes mellitus and hypertension, who had received as a result of drug misuse a 30mg lanreotide injection daily for 2 months. No acute symptoms or pharmacological signs of overdose were reported. One week after the last injection he experienced a myocardial infarction.

[2.7.4.5.5]

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Lanreotide is a synthetic octapeptide analogue of natural somatostatin. Somatostatin is an endogenous peptide present in several areas of the central nervous system and in the gastrointestinal tract. It has very powerful inhibitory effects on different cell types. Like natural somatostatin, lanreotide is a peptide inhibitor of numerous endocrine, neuroendocrine and exocrine mechanisms. It exhibits high affinity for both the somatostatin Type 2 (SSTR2) and Type 5 (SSTR5) receptors that are found in both the pituitary gland and pancreas, as well as in growth hormone-secreting pituitary tumours. Conversely, it has a much lower affinity for somatostatin 1, 3 and 4 receptors. This confers relative specificity of action on growth hormone secretion, making it suitable for the treatment of acromegaly. [2.7.2.1 / 2.7.2.2.1.2 / 2.7.2.3.1]

Pharmacodynamics

Primary pharmacology studies using lanreotide showed that lanreotide dose-dependently reduced spontaneous GH secretion in healthy volunteers and acromegalic patients. [2.7.2.3.5.1] Population PK/PD relationship between GH inhibition and lanreotide serum concentration was reported in two analyses including 129 and 107 patients respectively treated with Somatuline Autogel. Results from these studies indicated that lanreotide has a maximum capacity of GH inhibition of 82%. Lanreotide concentration providing half of the maximum inhibition of GH (EC50) in responder patients was 0.206 to 0.612 ng/mL and the median lanreotide serum level needed to decrease the GH to 2.5 ng/mL (C2.5) was 0.95 to 1.1 ng/mL. Non-responders do not respond to lanreotide treatment even with high lanreotide concentrations. [2.7.2.3.5.1] The potential for formation of lanreotide antibodies has been examined during the conduct of efficacy studies using lanreotide. Laboratory investigations showed that non-specific binding (NSB) >10% was present in a small minority of patients treated with lanreotide, and in a few patients the binding was specific for lanreotide and associated with serum antibodies. Somatostatin was not bound by any of the specimens tested. The safety profiles of patients with NSB values < 10%, between 10 and 30% and > 30% were similar and there was no evidence that any of the serious adverse events that were reported were due to hypersensitivity reactions. Clinical investigations failed to demonstrate any differences in response to lanreotide treatment between patients with NSB >10% or NSB >25% versus patients who did not exhibit NSB at these levels. [2.7.2.4.1]

Pharmacokinetics

Table 5a: Summary of Lanreotide's Pharmacokinetic Parameters in Healthy Volunteers After a Single Dose of Somatuline Autogel 60, 90 and 120mg

* = Median (range) value

Table 5b: Summary of Lanreotide's Pharmacokinetic Parameters in Acromegalic Patients After Four Doses of Somatuline Autogel 60, 90 and 120mg

*Median (range) value

PTF = Peak Trough Fluctuation

Distribution:

Studies with lanreotide after intravenous administration at doses of 7, 21 and 42

ug/kg have demonstrated that it shows limited extravascular distribution, with a mean Vss of 0.186 to 0.194 L/kg. Lanreotide human serum proteins binding studies were performed in vitro obtaining a range of values from 79 to 83 % at lanreotide concentrations between 12 and 60 ng/ml.

Metabolism: [2.7.2.2.2.3 / 2.7.2.3.3]

Lanreotide is metabolised extensively in the gastrointestinal tract after biliary excretion.

The values of apparent elimination half-life of Somatuline Autogel after deep s.c. administration range from 28 to 36 days. [2.7.2.3.2.1]

Excretion:

After a single s.c. dose of 3 mg of lanreotide, less than 1% of the administered dose was recovered in urine and renal clearance was < 1% of total plasma clearance. After s.c. infusion of lanreotide, the fraction of lanreotide excreted in the urine at steady state was 1% to 5% for a dose of 0.75 mg/day.

Data for fecal excretion showed that less than 0.5% of the administered dose was recovered over a 24 hour period at steady state. Therefore, urinary and faecal excretion of unchanged lanreotide represents only a small fraction of the total dose administered.. [2.7.2.3.2.2] No gender differences were found in PK parameters.

Special Populations and Conditions

Pediatrics: [-]

No studies in pediatrics were performed in this indication.

Geriatrics: [2.7.2.2.2.3 / 2.7.2.3.3]

Elderly subjects showed an increase in half-life and mean residence time compared with healthy young volunteers.

Hepatic Insufficiency: [2.7.2.2.2.3 / 2.7.2.3.3]

In hepatic impairment an increase in volume of distribution, mean residence time, AUC and half-life were observed. Clearance was reduced by 30% only in moderate to severe hepatically impaired patients, suggesting that clearance of lanreotide does not only depend on hepatic function.

Renal Insufficiency: [2.7.2.2.2.3 / 2.7.2.3.3]

In subjects with severe renal impairment total serum clearance of lanreotide is decreased approximately two-fold, with a consequent increase in half-life and AUC.

Although there are some differences observed in the pharmacokinetics of lanreotide in these populations, because lanreotide has a wide therapeutic window and dosage is titrated against reduction in GH and IGF-1, it is not considered necessary to alter the dosage recommendations. [2.7.2.3.3] (see Intrinsic Factor Pharmacokinetic Studies Section)

STORAGE AND STABILITY

Store under refrigeration (+2degC to +8degC) in its original package. Do not freeze. Shelf-life: 24 months [2.3.P.8.1]

SPECIAL HANDLING INSTRUCTIONS

Not applicable. [-]

DOSAGE FORMS, COMPOSITION AND PACKAGING

Somatuline Autogel is supplied in a polypropylene pre-filled syringe fitted with a stainless steel needle. [2.3.P.7] Each pre-filled syringe is packed in a nylon / polyethylene / aluminium laminated pouch. Box of one individual 60mg dose in a 0.3 ml syringe with a needle (1.2 mm x 20 mm). Box of one individual 90mg dose in a 0.3 ml syringe with a needle (1.2 mm x 20 mm). Box of one individual 120mg dose in a 0.5 ml syringe with a needle (1.4 mm x 20 mm). Somatuline Autogel is intended for deep subcutaneous injection. [2.3.P.1] The only excipient is water for injection. [2.3.P.2.1.2]

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Lanreotide acetate [2.3.S.1.1] Chemical name: [cyclo S-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D- tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate

[2.3.S.1.1]

Molecular formula: C54H69N11O10S2 (CH3COOH)x where x =1.6 to 3.2 [2.3.S.1.2] Molecular mass: 1096.34 g/mol (base) [2.3.S.1.2] Structural formula: S----------------------------S or x (CH3COOH) where x =1.6 to 3.2 Physicochemical properties: Appearance: White to practically white amorphous powder, odourless to faint odour of acetic acid. [2.3.S.1.3] Solubility: The solubility of lanreotide in aqueous solution varies little with pH, except at extreme pH values, most notably at alkaline pH. [2.3.S.1.3]

CLINICAL TRIALS

Study 717

The clinical efficacy of Somatuline Autogel was assessed in one pivotal clinical trial (E-28- 52030-717). The study was a randomized, double blind, placebo-controlled study, conducted in 108 acromegalic patients treated for one year. Half (50%) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for acromegaly three or more months prior to their participation in the study. For inclusion into study 717, these patients were required to have a mean GH level > 5 ng/mL at their first visit. The other 50% of the patients had received treatment with a somatostatin analog or a dopamine agonist prior to study entry (requiring an appropriate wash-out of this therapy before receiving the first injection of Somatuline Autogel). The median age of patients enrolled was 54.0 years with a range of 19-84 years. A similar number of males (n=51) and females (n=57) were treated and the median duration from diagnosis of acromegaly was approximately 3 years. Upon entry, patients were randomly allocated to receive a deep s.c. injection of Somatuline Autogel 60mg, 90mg or 120 mg or placebo (3:1). After the initial placebo controlled phase, patients entered a fixed-dose phase where they received injections of Somatuline Autogel at 4 week intervals for 4 injections, followed by a dose-titration phase of 8 injections (a total of 13 injections; including placebo phase). During the titration phase the dose could be adapted after 3 months according to the patients' individual GH and IGF-1 levels. [2.7.3.2.1.1]

Study results

Table 6. Results of study 717 in specific indication

DETAILED PHARMACOLOGY

Clinical pharmacodynamics

The dose and concentration of Somatuline Autogel was chosen with the help of results from an analysis of the relationship between lanreotide serum levels and GH plasma levels. This analysis was conducted using data from five clinical trials in which lanreotide was administered over a range of doses, routes and durations. The main finding from this analysis was that the concentration of lanreotide required to decrease the GH levels to 2.5 ng/mL was between 2 ng/mL and 3.5 ng/mL (60% to 81% of patients showed GH normalisation at these concentrations). Non-responders do not respond to lanreotide treatment even with high lanreotide concentrations. [2.7.2.3.5.1]

Secondary pharmacological effects

The secondary pharmacological effects of lanreotide are those observed with somatostatin analogs. Somatostatin is widely distributed in cells throughout the bodies of vertebrates and has pleiotropic actions. Therefore the effects of lanreotide on several physiological systems that are regulated by somatostatin such as inhibition of insulin, glucagons and somatostatin have been investigated. [2.7.2.3.5.2] Lanreotide provoked a physiological picture of slight glucose intolerance, characterized by decreased plasma levels of insulin and C-peptide and increased plasma levels of glucose. This effect was dose-related and attenuated over seven days of dosing. A study in patients with Type I or Type II diabetes mellitus evaluated the effects of a continuous, 21-day infusion of lanreotide. Lanreotide appeared to reduce the insulin requirements in patients with diabetes mellitus and had only a transient effect on blood glucose levels. [2.7.2.3.5.2] Five studies have been conducted to investigate the effects of lanreotide on digestive hormone secretions in healthy subjects. Similarly to somatostatin, lanreotide significantly reduced PP, motilin, and GIP levels (AUC values) and post prandial gastrin secretion, but did not affect secretin. [2.7.2.3.5.2] Somatostatin inhibits bile secretion and pancreatic secretion of bicarbonate and enzymes. Similarly lanreotide inhibited the volume of exogenously stimulated (secretin and CCK) pancreatic secretion and pancreatic bicarbonate and amylase secretion only on Day 2 after administration. Lanreotide did not significantly affect exogenously stimulated biliary secretion of bilirubin. Meal-stimulated secretion of amylase and bilirubin (AUC values) were significantly inhibited by lanreotide only on Day 2. [2.7.2.3.5.2] Somatostatin inhibits gastric acid secretion by inhibiting gastrin and by direct action on parietal cells. Lanreotide dose-dependently increased median gastric pH values and increased the duration of decreased acidity when given as a 24-hour infusion. [2.7.2.3.5.2] The human digestive tract and pancreas contain a large number of cells that secrete somatostatin. Somatostatin inhibits intestinal secretion of calcium, glucose, galactose, glycerol, fructose, xylose, lactose, amino acids, triglycerides, and water. [2.7.2.3.5.2] When studied, as expected, lanreotide significantly reduced PGE1-stimulated jejunal secretions of water, sodium, potassium, and chloride. [2.7.2.3.5.2] Somatostatin reduces blood flow to the small intestine. It inhibits mesenteric blood flow and restricts portal flow by constricting splanchnic blood vessels. Some studies have shown that GH and IGF-1 increase glomerular filtration rate (GFR) and renal plasma flow in healthy volunteers, and the somatostatin analogue octreotide decreased GFR in insulin-dependent diabetics and acromegalics. Three studies investigated the effects of lanreotide on renal and splanchnic blood flow in healthy subjects. [2.7.2.3.5.2] These studies showed that lanreotide decreases SMA and portal venous flow but has no effect on renal blood flow. [2.7.2.3.5.2] Inhibition of gallbladder contractility is a known effect of the drug class. The somatostatin analogue octreotide inhibits gallbladder contractility and facilitates formation of gallstones; approximately 18% of patients treated chronically develop either gallbladder sludge or stones. As expected, a single injection of lanreotide also significantly inhibited basal and post-prandial gallbladder contraction. [2.7.2.3.5.2]Somatostatin inhibits the release of thyroid-releasing hormone (TRH) in humans. This effect is readily observed in patients who are hypothyroid or who undergo stimulation with TRH. The three studies which investigated the effects of lanreotide on thyroid parameters confirmed that lanreotide administered as continuing infusion significantly inhibited nocturnal TSH in healthy volunteers and when administered repeatedly slightly affected TSH values compared to baseline in acromegalic patients. Somatostatin inhibits prolactin secretion. In cultured prolactinomas, this inhibition appeared to be mediated by the somatostatin receptor (SSTR) 5 receptor, but not the SSTR2 receptor. Prolactinomas appear to express only SSTR1 and SSTR5, and SSTR5 expression is correlated with prolactin regulation. Prolactin levels were measured in two studies conducted with lanreotide. In both of these studies, lanreotide treatment reduced prolactin levels. [2.7.2.3.5.2] Although acute administration of somatostatin strongly inhibits exocrine pancreatic secretions, divergent results have been published after prolonged treatment. Evidence from studies with the SST analogue octreotide suggests that the degree of inhibition of pancreatic secretion may decrease with continuing treatment. Inhibition of pancreatic enzyme secretion persisted after six days of treatment with the somatostatin analogue octreotide, but the degree of inhibition subsided from 80% to about 60% of control values, indicating an escape from the inhibitory effect of octreotide on CCK-stimulated enzyme secretion. A similar trend has been seen with acute and chronic administration of lanreotide. [2.7.2.3.5.2]

Clinical pharmacokinetics

Pharmacokinetics of Somatuline Autogel in Healthy Volunteers

Descriptive pharmacokinetic of lanreotide after Autogel deep subcutaneous administration was studied in healthy volunteers after a single administration. Results from this study show that the lanreotide release profile approximates log-linear following deep sc administration (Figure 1). [2.7.2.3.2.1]

Figure 1. Mean, overlaid, plasma concentration-time profiles of lanreotide (ng/mL) after deep sc administration of Somatuline Autogel T1, T2 and T3 (dose = 60, 90 and 120 mg, respectively)

Log

ng/ml

0 168 336 504 672 840 1008 1176 1344 1512 1680 1848 2016

Hours

Standard pharmacokinetic parameters monitored in this study following deep sc administration of Somatuline Autogel to healthy volunteers are summarised below. [2.7.2.3.2.1]

* = median and range in parenthesis

Both AUCt and AUC[?] increased with the dose; Cmax increased from 60 to 90 mg but at 120 mg an intermediate value was obtained. The high inter-subject variability observed for this parameter could explain why a dose relationship was not observed for Cmax. Some variability was also observed in tmax ranging between 2 and 48 hours, except in two volunteers who showed an unexpected value of 336 h. No important differences were observed in the median values obtained for these parameters (7 to 12 hours). The other parameters t1/2, tlag, MRT (Mean Residence Time), MAT (Mean Absorption Time) and F% showed similar values in the three dose groups. Mean t1/2 ranged from 664 to 860 hours (28 to 36 days) and bioavailability ranged from 78% to 83%. [2.7.2.3.2.1]

Pharmacokinetics of Somatuline Autogel in Patients with Acromegaly

The primary pharmacokinetic results for Somatuline Autogel are derived from a randomised, parallel-group, double-blind, single-center study that evaluated the pharmacokinetic profile of Somatuline Autogel administered at fixed doses of 60, 90, and 120 mg four times every 28 days in 18 patients with active acromegaly. [2.7.2.3.2.1] Following a single dose, the pharmacokinetics of Somatuline Autogel were dose-independent in the dose range 60 to 120 mg. Dose proportionality was observed in the pharmacokinetic parameters Cmin,1, Cmax and AUCt as shown in the table below. [2.7.2.3.2.1]

1. For this parameter, the median and range values were used

2. p value corresponding to pharmacokinetic parameters normalized by dose

Somatuline Autogel exhibited linear pharmacokinetics after repeated doses over the range of 60 to 120 mg administered once every 28 days (Table 9). Pharmacokinetic parameters Cmin,ss, Cmax,ss and AUCt increased in a dose-dependent linear manner. During the dosing interval, average steady state concentrations (Cavg) of 2.457, 3.040 and 4.523 ng *mL-1 were observed for the 60, 90 and 120 mg dose levels, respectively. [2.7.2.3.2.1]

Table 9. Comparative Mean (+- SD) Steady-State Pharmacokinetic Parameters Following Four Doses of Somatuline Autogel 60, 90 and 120 mg to Patients with Acromegaly

1. For this parameter, the median and range values were used

2. p value corresponding to pharmacokinetic parameters normalized by dose

Peak-trough fluctuation during the dosing interval was dose-independent in the dose range 60 to 120 mg, with values of 81%, 108% and 86% for the 60, 90 and 120 mg doses, respectively.

[2.7.2.3.2.1]

Four consecutive Somatuline Autogel administrations produced a slight accumulation independent of the dose level, with a mean accumulation index of approximately 2.7. This accumulation result is not unexpected considering the long half-life of Somatuline Autogel. [2.7.2.3.2.1] Following a single dose of Somatuline Autogel 60, 90 or 120 mg in Study 717, Cmin1 increased with lanreotide dose. The minimum serum levels after at least four consecutive lanreotide administrations at the same dose (steady-state) also increased with dose. Although the increase in Cmin,ss was slightly less than proportional to the dose for comparison of the 120 mg and the 60 mg doses in this study, no statistically significant differences by dose could be demonstrated when normalized by dose (Cmin ss/D). These results indicate that Somatuline Autogel exhibited linear pharmacokinetics in acromegalic patients over the range of 60 to 120 mg after four consecutive doses of Somatuline Autogel once every 28 days. Moderate accumulation of lanreotide in the body was also observed during this study at all dose levels, with mean accumulation indices (Rac) of 2.6, 3.2 and 2.8 for the 60, 90 and 120 mg doses, respectively.

[2.7.2.3.2.1]

The mean Cmax values following initial dosing with Somatuline Autogel were 2- to 4-fold higher than mean minimum serum levels after first Autogel administration (Cmin1), indicating that no initial burst effect is produced with this formulation for the three dose levels tested (60, 90 and 120 mg). Consistent observations were made after multiple deep s.c. injections. [2.7.2.3.2.1]

Excretion and Metabolism

Two studies examined the excretion of lanreotide. When lanreotide was given as a single sc dose of 3 mg, less than 1% of the administered dose was recovered in urine, and renal clearance was <1% of total plasma clearance. When lanreotide was given by sc infusion, the fraction of lanreotide excreted in the urine at steady state was 1% to 5% for a dose of 0.75 mg/day. Data for fecal excretion were collected in this study and less than 0.5% of the administered dose was recovered over a 24 hour period at steady state. [2.7.2.3.2.2] Therefore, urinary and fecal excretion represents only a small fraction of the total dose administered. This suggests that lanreotide is probably metabolised extensively in the gastrointestinal tract after biliary excretion. [2.7.2.3.2.2]

Intrinsic Factor Pharmacokinetic Studies

Pharmacokinetic studies have been conducted with lanreotide in patients with chronic renal failure, hepatic failure and in elderly subjects. [2.7.2.3.3]

Table 10. Summary of Lanreotide's Pharmacokinetic Parameters * in Special Populations[2.7.2.3.3]

*Lanreotide was administered intravenously as the immediate release formulation

Although some differences were observed in the pharmacokinetics of lanreotide in renal, hepatic and geriatric populations, because lanreotide has a wide therapeutic window, it is not considered necessary to alter the dose recommendations for Somatuline Autogel. [2.7.2.3.3] No gender differences were found in PK parameters.

Extrinsic Factor Pharmacokinetic Studies

The potential for interference between lidocaine and lanreotide was studied. The binding of lidocaine in serum varied from 78.84% to 68.28% when the concentration increased from 4 to 20 uM. Binding remained unchanged in the presence of 400 nM of lanreotide. This confirms that lanreotide, given its moderate total binding, its average affinity for acid alpha-1 glycoprotein (65000 M-1), and its very low therapeutic serum concentration (-100 nM), cannot displace other drugs bound to this protein. [2.7.2.3.4] The potential for drug-drug interactions of lanreotide between Somatuline Autogel and cyclosporin and vitamin K has been evaluated. Lanreotide decreased the bioavailability of oral cyclosporin by approximately 20%. No significant interaction with vitamin K was observed. [2.7.2.3.4] Literature comparisons of lanreotide with Sandostatin and Somatostatin UCB show that the principal pharmacodynamic interaction that may occur is the inhibition of glucagon secretion which may lead to the onset of hypoglycemia in treated diabetic patients, notably insulin- dependent patients. Thus, the insulin requirements in insulin-dependent diabetic patients may be reduced. [2.7.2.3.4]

MICROBIOLOGY

Not applicable

TOXICOLOGY

An immediate-release formulation (IRF) of lanreotide, administered either by sc injection or as an iv infusion was used for most of the toxicology studies. This allowed considerably higher doses to be achieved than would have been possible with the Autogel formulation.

Single Dose Toxicity Studies [2.4.4.2 / 2.6.6.3.1]

Table 11 : Summary of lanreotide single dose toxicity studies

The results of the single dose i.v. and s.c. studies indicated that both rodent species were able to tolerate large doses of lanreotide. There was no evidence of organ specific toxicity.

Repeat Dose Toxicity Studies [2.4.4.2 / 2.6.6.3.1]

Table 12 : Summary of lanreotide repeat dose toxicity studies

The toxicological effects associated with repeated subcutaneous, intramuscular and intravenous administrations were assessed in mice and/or rats and dogs (see Table above). Chronic toxicity was assessed in the rat and in the dog. The results of these studies revealed no evidence of target organ toxicity. Inhibition of growth rates observed at high doses was considered to be secondary to lanreotide's recognized pharmacologic effect, inhibition of growth hormone secretion. Similarly, lanreotide-associated reductions in serum concentrations of some hormones were considered to be extensions of the pharmacologic effect. Continuous infusion of lanreotide to dogs for up to 45 days was associated with dose-related testicular immaturity in males. Control animals also had immature testicles but the degree of immaturity appeared to increase in a dose- related fashion and was consistent with the general growth retardation of lanreotide treated animals. With the exception of dose-related irritation at the site of injection, lanreotide was well tolerated by all test species and the results indicate little, if any, potential for chronic administration of the drug in humans to produce target organ toxicity.

Chronic Toxicity Studies [2.4.4.3 / 2.6.6.3.2]

Table 13 : Summary of lanreotide chronic toxicity studies

The chronic toxicity of subcutaneously administered lanreotide was assessed in a 24 months study in rats. The results of this study were similar to those of shorter-term repeated dose studies in that there was no evidence of systemic, organ specific toxicity. Further, there was no evidence that lanreotide influenced the incidence or rate of onset of spontaneously occurring neoplasms in this strain of rats. Chronic toxicity (24 months) was also assessed in dogs. The results of this study corroborated the absence of significant systemic toxicity observed in dogs after shorter-term repeated dose studies.

Genotoxicity [2.6.6.4]

Table 14: Summary of In Vivo and In Vitro Mutagenicity Studies

The standard battery of genotoxicity tests were performed. In this set of studies, no positive results were obtained.

Carcinogenicity

Carcinogenicty studies have not been conducted with lanreotide. However, in the chronic toxicology study in rats (24 months), the incidence and type of neoplasms were similar in the treated and control groups.. This and the lack of evidence for mutagenic activity suggest that there are no concerns over carcinogenicity with lanreotide. [2.6.6.5]

Reproductive Toxicity

The high dose somatostatinergic effects of lanreotide on the secretion of pituitary hormones can be expected to cause perturbations of reproduction. The effects of lanreotide on mating behaviour and reproductive performance were assessed in male and female rats by administering the drug by the s.c. and/or i.m. routes. [2.4.4.4 / 2.6.6.6] Although administered at doses sufficiently high to reduce growth rates of both males and females of the F0 generation neither mating behaviour nor reproductive performance were adversely affected. The behavioural and reproductive characteristics of the F1 and F2 generations were similarly unaffected by administration of lanreotide to the parental generations. [2.4.4.4] Teratological potential was assessed by daily administering s.c. doses of lanreotide (0, 100, 450, or 2000 mcg/kg) to pregnant rats (from gestation day 6 to 15) and rabbits (from gestation day 6 to 18). The doses were selected on the basis of preliminary dose range finding studies, at doses up to and including 5000 mcg/kg/day, which are included within the documentation. Female rats administered the 2000 mcg/kg dose exhibited decreased weight gains but there was no evidence of either foetal toxicity or teratological anomalies. In rabbits, all dosed groups had reduced body weight gains and there was evidence of foetal toxicity (increased post implant loss in the 450 and 2000 mcg/kg groups) but no evidence of either soft tissue or skeletal anomalies. [2.4.4.4]

Local Tolerance

Specific tolerance studies with the Somatuline Autogel formulation have been conducted, and are summarized below. [2.6.6.7]

Local tolerance testing involved following animals for up to 150 days after s.c. or i.m. injection, in single and multiple dose studies. Local tolerance was adequate to support the prolonged intermittent use of Somatuline Autogel in patients. Findings can be summarized as follows. The local tolerance on i.m. and s.c. injection was acceptable. Local tolerance studies of the Autogel formulation proposed for marketing showed a locally restricted response with development of a fibrous capsule at the injection site. The response was not severe and is likely to be similar to the effects of injecting other biocompatible materials. No general adverse reactions were observed and there was no difference in local tolerance after multiple doses compared to single injections.

Immunotoxicity

Provision was made to assess the potential to adversely affect lymphocytes, macrophages and natural killer cells during the course of a 45-day continuous i.v. infusion toxicity study in beagle dogs. No effects were found at doses of 0.4, 4 or 10 mg/kg to indicate that lanreotide has any potential to modify the selected immunotoxicity end-points. [2.4.4.8.1] Lanreotide is a small peptide whose molecular weight is below the approximate 10000 minimum for antigenicity independently of any haptenic function. Neither modifications of the hematology parameters nor lesions of the lymphoid organs, which may be indicative of immunostimulation, were observed in treated rats and dogs. [2.4.4.8.1] Blood samples obtained from rats after 26 weeks and 24 months of daily s.c. administration of lanreotide at doses of 0, 8, 40 and 120 mcg/kg/day tested negative for anti-lanreotide antibodies. Thus no evidence was obtained in these studies to conclude that lanreotide has any immunogenic potential when repeatedly administered to rats for prolonged periods. [2.4.4.8.1]

REFERENCES

1. Phase II, multi-centre, randomised, double-blind study, in acromegalic patients evaluating the efficacy and safety of a single deep subcutaneous administration of lanreotide autogel (60, 90, or 120 mg) versus placebo, followed by a single-blind fixed dose phase evaluating the pharmacokinetic, pharmacodynamic, efficacy and safety profile of multiple deep subcutaneous administrations of lanreotide autogel (60, 90 & 120 mg) ending in open label dose titration phase. Study E28 52030 717. Data on file. Beaufour Ipsen Pharma 2004.

PART III: CONSUMER INFORMATION

SOMATULINE(r) AUTOGEL(tm)

lanreotide injection

60, 90, 120mg lanreotide (as acetate)/unit (syringe)

This leaflet is part III of a three-part "Product Monograph" published when Somatuline Autogel was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Somatuline Autogel. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Somatuline(r) Autogel(tm) is recommended for the treatment of acromegaly.

What it does:

Somatuline Autogel is a long-acting formulation of lanreotide that lasts for 28 days. Lanreotide is similar to the naturally occurring hormone somatostatin. Lanreotide lowers the levels of hormones in the body such as GH (growth hormone) and IGF-1 (insulin-like growth factor-1) and inhibits the release of some gastrointestinal hormones and intestinal secretions.

When it should not be used:

Somatuline Autogel should not be used if you have previously been allergic to lanreotide or any other drug like somatostatin; or if you have untreated gallstones in the bile duct with symptoms such

as severe pain in the abdomen, accompanied by nausea and

vomiting.

What the medicinal ingredient is:

lanreotide acetate

What the important nonmedicinal ingredients are:

The only excipient is water for injection.

What dosage forms it comes in:

Somatuline Autogel is packaged in a pre-filled syringe, ready to be injected. It is available in three strengths of 60 mg, 90 mg and 120 mg.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• If you are a diabetic, your doctor may check your blood sugar levels and possibly change your treatment

• Due to the possible formation of gall stones, your doctor

may want to do a gall bladder scan at start of treatment and periodically thereafter

If you are taking cyclosporin, your doctor should check your

blood levels more often (as they may be lower)

BEFORE you use Somatuline Autogel talk to your doctor or pharmacist if:

• you are taking any other medicines

• if you are diabetic

• you have ever experienced liver or kidney problems

• you have ever experienced heart problems

• you have ever experienced gall bladder problems

• you are pregnant, planning to become pregnant, or breast-feeding

• you have previously been allergic to lanreotide or any

other drug like somatostatin

INTERACTIONS WITH THIS MEDICATION

The gastrointestinal effects of lanreotide may reduce the intestinal absorption of any other medicinal products that you are taking. Drugs that may interact with Somatuline Autogel include: cyclosporin, bromocriptine. Blood glucose levels may be affected by Somatuline Autogel.

PROPER USE OF THIS MEDICATION

Usual Adult Dose:

The recommended starting dose is an injection of Somatuline Autogel 90 mg. You will normally be given one injection every 28 days. After 3 months your doctor may change the dose of your

injections, depending on how your symptoms and hormones are

responding to the product.

Somatuline Autogel is given as a deep subcutaneous (deep under the skin) injection at varying places in your buttock.

Overdose:

As your doctor will give you one injection every 28 days, overdose is unlikely. If you have any concerns about the amount of drug you have received, talk to your doctor.

Missed Dose:

As soon as you realise that you have missed an injection, contact your doctor. Your doctor will then be able to give you your next

injection.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, Somatuline Autogel can have side effects. In clinical trials with Somatuline Autogel, the injections were generally well tolerated and most side effects were mild to moderate in intensity. The most frequently reported side effects were gastrointestinal including:

• diarrhea (loose stools)

• gall bladder stones

• abdominal pain

• nausea

• flatulence (wind),

Other side effects occurring less frequently included: Common events (Occurs in between 1:10 and 1:100 patients) abnormally low or high blood sugar levels; loss of appetite; indigestion; dizziness; decreased heart rate ; tiredness; injection site reaction. Uncommon events (Occurs in between 1:100 and 1:1000 patients) worsening of diabetes mellitus (for patients with this condition); acute inflammation of the pancreas (acute pancreatitis); fatty stools; allergic skin reactions; hair loss; and hard swelling at the injection site. Rarely, persistent hard swelling at the injection site has been reported.

This is not a complete list of side effects. For any unexpected effects while taking Somatuline Autogel, contact your doctor or pharmacist.

HOW TO STORE IT

Store Somatuline Autogel at 2oC-8oC in a refrigerator in its original package. Do not freeze. Keep out of the reach and sight of children. Do not use after the expiry date shown on the labels and box.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be obtained by contacting the sponsor, Ipsen Ltd, at: 1-800-478-0144

This leaflet was prepared by Ipsen Ltd. Last revised: July 13, 2006.