Summary Basis of Decision for Somatuline ® Autogel ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Somatuline® Autogel®
Lanreotide (as lanreotide acetate), 60 mg, 90 mg, 120 mg lanreotide / unit (syringe), Extended-release supersaturated solution, Deep subcutaneous injection
Ipsen Ltd.
Submission control no: 098949
Date issued: 2007-03-06
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrSOMATULINEMD AUTOGELMD, Lanréotide, 60 mg, 90 mg, 120 mg/dose unitaire (seringue), Solution sursaturée à libération prolongée, Ipsen Limited, N° de contrôle de la présentation 098949
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02283395 - 60 mg/unit
- 02283409 - 90 mg/unit
- 02283417 - 120 mg/unit
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control No. 098949
Date of Submission:
Date of authorization:
2 Notice of decision
On July 17, 2006, Health Canada issued a Notice of Compliance to Ipsen Limited for the drug product Somatuline Autogel.
Somatuline Autogel contains the medicinal ingredient lanreotide which is an anti-growth hormone.
Somatuline Autogel is indicated for:
- long-term treatment of patients with acromegaly due to pituitary tumours who have had inadequate response to or cannot be treated with surgery and/or radiotherapy;
- relief of symptoms associated with acromegaly.
Lanreotide is a peptide inhibitor of numerous endocrine and neuroendocrine effects of growth hormone. The goal of treatment in acromegaly is to reduce growth hormone (GH) and age adjusted insulin-like growth factor 1 (IGF-1) levels and, where possible, to achieve normalization of the values.
Market authorization was based on submitted data from quality control studies, pre-clinical and clinical studies. Clinical efficacy and safety were assessed in one pivotal, randomized, double-blind, placebo-controlled study conducted in 108 acromegalic patients treated for one year.
Somatuline Autogel [60mg, 90 mg, 120 mg lanreotide (as acetate)/unit (syringe)] is an extended-release supersaturated solution presented in pre-filled syringes which are ready to use. Patients should begin treatment with 90 mg given via deep subcutaneous route, at 4-week intervals for 3 months. After 3 months, the dosage should be adjusted according to the response of the patient as judged by the reduction in symptoms and/or in GH and/or in IGF-1 levels. Dosing guidelines are available in the Product Monograph.
Somatuline Autogel is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container, patients who are hypersensitive to somatostatin or related peptides, and patients with complicated, untreated lithiasis of the bile ducts. Somatuline Autogel should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Somatuline Autogel are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Somatuline Autogel is favourable for the long-term treatment of patients with acromegaly due to pituitary tumours who have had inadequate response to or cannot be treated with surgery and/or radiotherapy, and for the relief of symptoms associated with acromegaly.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
The drug substance, lanreotide (as lanreotide acetate), is synthetically derived. Materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Appropriate specifications for all of the starting materials were provided. None of the materials used represent a risk of transmission of Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) agents.
Characterisation
A number of studies have been conducted to confirm the structure and other characteristics of lanreotide. Each of the amino acids in lanreotide contains at least one chiral centre; therefore a number of linear and cyclic diastereoisomers could potentially be formed. Suitable in-process controls and reaction conditions have been applied to assure the formation of the drug substance.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were adequately qualified from toxicology studies and batch analyses; and therefore considered acceptable.
Control of Drug Substance
Test results for 14 batches were provided. Data from the batch analyses were reviewed and considered to be acceptable according to the specification of the drug substance. The validation studies and the batch analyses presented demonstrate that appropriate specifications have been applied.
The container closure system used for storage and transport of the drug substance is considered acceptable.
Stability
Stability data of lanreotide under the recommended storage conditions indicate that the water content, acetate content, peptide content, and impurities are within the proposed specifications.
3.1.2 Drug Product
Description and Composition
The drug product, Somatuline Autogel, is a pre-filled syringe containing a white to pale yellow lanreotide supersaturated solution having a lanreotide base of 24.6% w/w. The formulation consists of the drug substance, lanreotide acetate (a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin), and water for injection. The polypropylene pre-filled syringe is fitted with a stainless steel needle, covered by a sheath and is packed in a nylon/polyethylene/aluminum laminated pouch.
Somatuline Autogel is presented in three doses as single, sterile, ready to use, pre-filled syringes intended to deliver 60, 90, or 120 mg lanreotide (potency is expressed as lanreotide base). The different doses are dose proportional, i.e., the greater the potency, the greater the filling quantity in the syringe. The sizes of the syringe and needle differ for the 120 mg dose. The three doses are presented as follows:
- Box of one individual 60 mg dose in a 0.3 mL syringe with a needle (1.2 mm x 20 mm).
- Box of one individual 90 mg dose in a 0.3 mL syringe with a needle (1.2 mm x 20 mm).
- Box of one individual 120 mg dose in a 0.5 mL syringe with a needle (1.4 mm x 20 mm).
Pharmaceutical Development
Changes to the manufacturing process and formulation throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacture of the pre-filled syringes of Somatuline Autogel 60, 90, and 120 mg, is a simple procedure consisting of mixing lanreotide acetate with water for injection to form a supersaturated solution. The supersaturated solution, having a lanreotide base content of 24.6% w/w, is then filled into either 0.3 mL or 0.5 mL polypropylene syringes (depending upon the intended doses).
Needles and needle sheaths are fixed in place and final pre-filled syringes are packaged and terminally sterilized by gamma irradiation.
Manufacturing equipment and materials used throughout the process are in compliance with Good Manufacturing Practices recommendations for pharmaceutical use. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
The routine control tests on the drug product include a range of tests typical for peptide and injectable products: general appearance, identification, injectable dose, concentration, dose uniformity, purity, endotoxins, pH, and in vitro dissolution. All analytical methods have been properly validated.
Data from final batch analyses were reviewed and considered to be acceptable according to the specification of the drug product. The proposed specifications for impurities in the dosage form are considered acceptable.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, considered to be acceptable.
Stability
Based upon the long term and accelerated stability data submitted, the proposed shelf life of 2 years at 2-8°C is considered acceptable for the product when packaged in a polypropylene syringe with a bromobutyl rubber plunger stopper and stainless steel needle.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Somatuline Autogel has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Lanreotide demonstrated a high affinity for binding to somatostatin receptors isolated from laboratory animals as well as cloned human receptors. Lanreotide exhibited selectivity with respect to receptor sites and acted as an agonist on the somatostatin receptors. The results of the growth hormone (GH) release inhibition studies in both rats and monkeys indicated that lanreotide is a potent inhibitor of the release of GH. The results of these experiments are consistent with the in vitro binding studies demonstrating that lanreotide is a potent and specific binder to somatostatin receptors in the anterior pituitary.
Many experiments were conducted to assess the effects on the body systems. The results of the in vitro and in vivo studies demonstrated the following characteristics:
- Lanreotide had essentially no affinity for other bioreceptors although it did bind to the mu morphine receptor isolated from guinea pig brain. The characteristics of this binding suggest that the drug may possess morphine antagonism activity.
- Lanreotide showed a significant interaction with estradiol, leading to an inhibitory effect on hyperprolactinemia.
- Subcutaneously administered lanreotide was approximately 50% less active than either somatostatin or octreotide in inhibiting glucose stimulated insulin secretion.
- Repeated doses of lanreotide increased gall bladder weight suggesting that the drug may increase the risk of gallstone formation in some patients.
- The absence of effects of lanreotide on the central nervous system predicts that the drug will produce few, if any neurological or behavioural effects in humans.
- Lanreotide produced transient non-dose dependent hypotension immediately after injection. The 80 µg/kg dose caused a transient bradycardia (40 beats/min) which persisted for about one minute but this effect was not observed after the low 20 µg/kg dose. Lanreotide produced no changes in ECG nor were there changes in blood gases or pH. Both doses of lanreotide caused transient (one minute) decreases in respiratory amplitude but there were no changes in respiratory rate.
- In vitro studies indicated that lanreotide does not produce significant inhibition of HERG tail current nor has a significant effect on action potentials of Purkinje fibers. Evaluation of the QT prolongation in vivo revealed the changes in T wave morphology to be a consequence of the effect of lanreotide on cardiac chronotropism rather than an electrophysiological effect. No arrhythmia attributable to lanreotide was observed at any dose level.
- Intradermal injections of high doses of lanreotide caused significant, dose-dependent inflammatory cutaneous reactions at the sites of injection.
The results of these experiments support the proposed use of lanreotide in the treatment of acromegaly and the anticipated side effects are similar to those produced by the clinically available drug, octreotide.
3.2.2 Pharmacokinetics
The absorption, distribution, metabolism, and excretion of lanreotide were studied in rats and dogs after intravenous, subcutaneous, and intramuscular administration. Data on the immediate release (IRF) lanreotide (lyophilised peptide dissolved in saline) and the extended-release supersaturated solution of lanreotide were reviewed.
Absorption
Lanreotide is quickly and efficiently absorbed from either subcutaneous or intramuscular sites.The supersaturated solution had an absolute bioavailability of approximately 91-93%. Dose-dependent pharmacokinetic parameters of lanreotide were linear except at high doses.
Distribution
After subcutaneous administration, radiolabelled lanreotide was initially concentrated in the liver, kidneys, pancreas, and lungs. Maximum concentrations of radioactivity were detected in most tissues (pancreas, bone marrow, salivary and lachrymal glands, glandular stomach wall, adrenals, kidney, liver, and thymus) at the 24-hour time period and similar distribution but lower tissue concentrations were observed at 168 hours.
Metabolism
Lanreotide was extensively metabolized in the gastrointestinal tract after biliary excretion.
Excretion
The primary route of elimination of lanreotide in rats and dogs was biliary (faeces) with urinary excretion (5%) representing a secondary route.
There was no evidence of bioaccumulation of lanreotide after administration by repeated subcutaneous or intramuscular injection, or by intravenous infusion.
3.2.3 Toxicology
Acute Toxicity
Lanreotide demonstrated a relatively low acute toxicity when administered by parenteral routes to rodents; therefore based on these studies a wide margin of safety for acute toxicity in humans is predicted. Acute toxicity studies in non-rodent species were not conducted.
Long-Term Toxicity
Overall, the general repeat-dose toxicity studies conducted in mice, rats and dogs using several parenteral routes of administration did not reveal any significant or remarkable systemic toxicity for lanreotide. At the injection sites, however, dermal toxicity was observed in a dose-related manner in all species studied. These local reactions included skin irritation, infiltration by inflammatory cells, and occasional granulomatosis.
Although histopathological examinations demonstrated degeneration and atrophy in lymphatic tissues such as the thymus, and in testes of animals treated with relatively high doses of lanreotide, no actual immunotoxicity or impaired reproductive functions were observed.
Genotoxicity
No genotoxic activity for lanreotide was demonstrated in the battery of mutagenicity tests. Therefore, lanreotide is considered to have no genotoxic potential.
Carcinogenicity
No carcinogenicity studies were provided.However, no evidence for carcinogenic potential of lanreotide was observed in the chronic toxicity study with rats. This and the lack of evidence for genotoxic activity suggest that there is no concern for carcinogenic potential with lanreotide.
Reproductive and Development Toxicity
Repeated doses of lanreotide produced no evidence of reproductive toxicity in male or female rats, despite some degenerative changes that occurred in the male reproductive organs. No evidence of skeletal or soft tissue malformations were observed in the developmental studies with rats or rabbits, however high doses of lanreotide have caused embryotoxicity/lethality in animals. Therefore, it can be anticipated to have the potential for embryotoxicity in humans.
Local Tolerance
Overall, the local tolerance studies, in addition to the general toxicity studies, have provided evidence that lanreotide is clinically well tolerated in animal studies and only moderate and transient signs of inflammation can be anticipated at the injection sites in humans.
Impurity Evaluation
The impurities present in the drug product have been qualified through animal and human exposure and the levels presented are demonstrated to be safe.
3.2.4 Summary and Conclusion
When administered in either single or repeat-dose regimens, lanreotide was well tolerated in all animal species tested, and possesses little, if any, potential for producing organ-specific systemic toxicity.
Overall, it is concluded that there is sufficient toxicity data submitted to predict the safe use of lanreotide in patients with acromegaly.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic (PD) studies examined both primary (inhibition of GH and IGF-1) and secondary effects of lanreotide. The clinical data demonstrated that lanreotide significantly decreased levels of GH and IGF-1. The reduced number and intensity of GH peaks were dose-dependent.
In patients with acromegaly, the mean reduction in GH was 16% after having the immediate release (IRF) lanreotideadministered subcutaneously (SC) by pump for 14 weeks. The mean reduction in IGF-1 levels was 14% at the end of the study.Lanreotide levels up to 3.5 ng/mL were estimated to be necessary to achieve mean GH levels below 2.5 ng/mL in 81% of the patients with acromegaly.
Results from the population PD study indicated that the median lanreotide serum level needed to decrease the GH to 2.5 ng/mL in lanreotide responder patients was 0.95 ng/mL, and the median GH concentration reached asymptotically when lanreotide concentration trends to infinity was 1.71 ng/mL. Non-responders did not respond to lanreotide treatment even with high concentrations of lanreotide.
The secondary pharmacological effects of lanreotide were consistent with the effects expected from a somatostatin analogue. Somatostatin (the naturally produced GH release inhibitor) is widely distributed in cells throughout the bodies of vertebrates and has pleiotropic actions. These include effects on several physiological systems: glycoregulation, secretion of digestive hormones, intestinal transit, renal and splanchnic blood flow, and secretion of other hormones (e.g., cortisol). In all cases, the effects of lanreotide were consistent with those of somatostatin.
The potential for formation of lanreotide antibodies was examined during the efficacy studies. The safety profile of patients with non-specific binding (NSB) values of <10%, 10-30%, and >30% were similar and there was no evidence that any of the serious adverse events that were reported were due to hypersensitivity reactions. The efficacy data from patients with NSB >10% showed no differences in response to treatment in terms of control of GH or IGF-1 levels compared to patients who did not exhibit NSB at these levels.
3.3.2 Pharmacokinetics
The absorption, distribution, metabolism and excretion of lanreotide were studied in healthy volunteers and patients with acromegaly. The pharmacokinetic (PK) analysis is based on the characteristics of IRF lanreotide (lyophilised peptide dissolved in saline) and the extended-release supersaturated solution of lanreotide.
Absorption
After single-dose lanreotide IRF subcutaneous (SC) administration, the absorption rate was relatively high, with a tendency to decrease after the administration of the higher doses. The absolute bioavailability was 82.84±23.48%, but there was large inter-subject variability. Steady state was linear between 7 µg/kg/8h and 21 µg/kg/8h at up to 10 doses.
The PK of the supersaturated solution of lanreotide administered SC was long lasting and linearly related to dose in the dose range 60-120 mg in healthy volunteers and patients with acromegaly. The serum concentration of lanreotide IRF (SC) showed a long lasting behaviour (still present in most volunteers on study day 84).
The absolute bioavailability was 83.25±34.56 (60 mg), 78.14±25.87 (90 mg), 80.87±24.18 (120 mg) dose. Four consecutive administrations of the supersaturated solution produced a slight accumulation in the body 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 the drug product. Peak-trough fluctuation (PTF) during the dosing interval was dose-independent in the dose range 60 to 120 mg, with values of 81%, 108% and 86% for 60, 90 and 120 mg, respectively. The PK data confirmed that minimal dose-dumping occurred after the fourth dose of the drug.
Distribution
Extravascular distribution of lanreotide was minimal.
In vitro studies with lanreotide concentrations of 12-60 ng/mL demonstrated that the binding of radiolabelled lanreotide to serum proteins was 79-83% in humans.
Metabolism
Results from clinical studies support that lanreotide is extensively metabolized in the gastrointestinal tract as observed in the preclinical studies.
Excretion
The PK results indicate biliary excretion with degradation of lanreotide in the intestines. The immunoreactivity recovered in urine and faeces was only a small fraction of the total lanreotide dose administered. The appearance of unchanged lanreotide in the faeces is indicative of biliary excretion of lanreotide.
Special Populations
Renal Impairment - Drug exposure was higher in patients with severe chronic renal insufficiency than in healthy subjects. Total serum clearance values were reduced about 2-fold in patients with severe chronic renal insufficiency compared to those in healthy subjects.
Hepatic Impairment - Increases in volume distribution and drug exposure values were observed in patients with mild to severe liver disease. Clearance was reduced by 30.9% in patients with hepatic impairment compared to healthy subjects.
Dose adjustments are not required for patients with renal or hepatic impairment as there appears to be no safety concerns, and the dosage is determined by the reduction of GH and IGF-1.
3.3.3 Clinical Efficacy
The clinical efficacy of 60, 90, and 120 mg Somatuline Autogel was assessed in one pivotal, multicentre, randomized study conducted in 108 patients with acromegaly who may or may not have been previously treated with surgery and/or radiotherapy. Patients who had also previously been treated by somatostatin analogues or dopamine agonists were subject to a 12-week wash-out period.
The study consisted of four distinct phases: the wash-out phase; the double-blind placebo-controlled phase (weeks 0-4, single injection); the single-blind, fixed-dose phase (weeks 4-20, four injections based on dose group); and the open-label dose titration phase (weeks 20-52, eight injections). A combination of GH and IGF-1 measurements were needed to accurately evaluate the response to treatment. The criterion for control of acromegaly was GH <2.5 ng/mL and normalization for age adjusted IGF-1.
At week 4, single injections of 60, 90, and 120 mg Somatuline Autogel were more effective than placebo in reducing mean GH and IGF-1 levels. The primary efficacy endpoint, the proportion of patients with a decrease in mean GH of >50% from baseline to week 4, was 44-90%.
The results of the secondary efficacy endpoints are listed below:
- The proportion of patients with mean GH≤2.5 was 19% in the 60 mg dose group and 52% in the 120 mg dose group, with the overall proportion of patients at 34% compared to 0% with placebo.
- The proportion of patients with normalized IGF-1 (adjusted for age) was 17-30% compared to 4% with placebo.
- The proportion of patients with mean GH≤2.5 and normalized IGF-1 (adjusted for age) was 11-19% compared to 0% with placebo.
Results from the other phases of the study, (i.e., weeks 4-52) support the 4-week data.
- The proportion of patients with a decrease in mean GH from baseline >50% at weeks 16, 32, 52 (actual visit) and 52b (for early withdrawal), and the last value available post-baseline (LVA) was significant. At the entry into the dose-titration portion of the study, 73% of patients had a decrease in mean GH of >50% from baseline. The proportion of patients with this level of response increased to 80% and 82% at weeks 32 and 52, respectively, indicating continued response to treatment when the dose could be adjusted more than once. At LVA, 77% of the patients had a decrease in mean GH of >50% from baseline.
- None of the patients entered into the open-label phase with mean GH <2.5 ng/mL. At week 16, 50% of the patients had mean GH levels <2.5 ng/mL. At weeks 32 and 52 the percentage increased to 57% and 54%, respectively. At LVA, 51% of the patients had mean GH <2.5 ng/mL.
- 8% of the patients entered the open-label phase with normalized IGF-1 levels. At week 16, 55% of the patients had normalized IGF-1 levels. At weeks 32 and 52, the percentage was maintained at 55% and increased to 59%, respectively. At LVA, 57% of the patients had normalized IGF-1 levels.
- None of the patients entered the study with mean GH <2.5 ng/mL and normalized IGF-1. At week 16, 39% of the patients had mean GH <2.5 ng/mL and normalized IGF-1. At weeks 32 and 52, the percentage increased to 45% and 43%, respectively. At LVA, 41% of the patients had mean GH <2.5 ng/mL and normalized IGF-1.
The changes in GH and IGF-1 were accompanied by "improvement from baseline" or "stability" in the following acromegaly symptoms: headache, perspiration, fatigue, swelling of extremities, and joint pain (observed in 92% to 93% of patients at entry into the dose-titration portion of the study). At LVA, these symptoms had improved from baseline or were stable in 88% to 94% of patients indicating continued response to treatment during the dose-titration phase. No trends in symptom improvement were noted with increasing the dose of lanreotide.
3.3.4 Clinical Safety
The clinical safety of Somatuline Autogel was assessed in one pivotal study conducted in 108 acromegalic patients treated for one year. For a description of the study, see section 3.3.3 Clinical Efficacy.
During the double-blind phase of the study (weeks 0-4), a higher proportion of patients in the Somatuline Autogel treatment groups (60%) experienced at least one treatment-emergent adverse event compared to the placebo group (36%).
Within all of the Somatuline Autogel dose groups, the incidence of reported adverse events during the double-blind phase was 41%, 70% and 69% for the 60, 90 and 120 mg treatment groups, respectively. The most common adverse events during this phase were diarrhoea (31% vs. 0% of lanreotide-treated and placebo-treated patients, respectively), abdominal pain (7% vs. 4%), bradycardia (8% vs. 0%), weight decrease (8% vs. 0%), anaemia (7% vs. 0%) and flatulence (6% vs. 0%). Among these events only diarrhoea and flatulence exhibited an increased incidence across lanreotide doses.
The most common adverse events during lanreotide treatment across all three study phases were diarrhoea (48%), cholelithiasis (30%), abdominal pain (21%), bradycardia (14%), arthralgia (13%), anaemia (12%), alopecia (12%), injection site mass (10%), flatulence (10%) and nausea (10%). The incidence of diarrhoea (22%, 29%, and 47% for the 60, 90, and 120 mg groups, respectively), abdominal pain (11%, 14%, and 15%, respectively), and flatulence (4%, 5%, and 9%, respectively) increased with lanreotide dose. In addition, the incidence of cholelithiasis (17%, 14%, and 24% for the 60, 90, and 120 mg groups, respectively) and injection site mass (4%, 3%, and 11%, respectively) was highest during treatment with 120 mg. The majority of adverse events reported during lanreotide treatment across the three study phases were mild to moderate in severity. A total of 32 (30%) of the 107 lanreotide-treated patients experienced adverse events judged to be severe in intensity by the investigator including 15%, 17%, and 23% of patients during treatment with 60, 90 and 120 mg lanreotide, respectively. The most common adverse events of severe intensity were abdominal pain (7%) and diarrhoea (6%).
There were no deaths reported during the study. Eighteen (17%) of the 107 lanreotide-treated patients experienced serious adverse events (SAEs) during the three study phases including 9%, 12%, and 11% of patients during treatment with 60, 90 and 120 mg, respectively. Only one SAE, pancreatitis associated with gallbladder lithiasis migration, was judged to be related to study-treatment by the investigator.
Four patients withdrew from the study due to treatment-emergent adverse events. None of these events were assessed as drug-related by the investigator.
No clinically meaningful changes in hematology, chemistry, or vital sign parameters were associated with Somatuline Autogel following repeated injections through 52 weeks of treatment.
Mean quantitative cardiac electrophysiologic and chamber dimensions were within normal limits for a population of patients with acromegaly and did not appear to show any major changes over time. Lanreotide-treated patients had a decrease in heart rate and concomitant changes in the ECG intervals that follow heart rate. Cardiac dimensions were unchanged other than a minor decrease in left ventricular septal and posterior wall thickness and left ventricular cavity which corresponded to a decrease in left ventricular mass that was not statistically significant. This reduction was concordant with a change in body size. The valvular regurgitations seen in this population were typical of a population of patients with acromegaly and did not appear to show any clinically meaningful changes over time.
Gallbladder ultrasound revealed that the incidence of new onset of lithiasis and sludge by study end was approximately 16% of patients with data available at baseline and post-baseline. Patients whose last dose administered was 120 mg appeared more likely to have new onset of lithiasis and sludge (20%) compared to patients who received the lower doses (<10%).
Post Marketing Experience
The safety update reports covering the time period from 2001 until July 2004 do not indicate an increased incidence of known side effects or change in their severity, nor unexpected side effects during this post marketing period.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Treatment with Somatuline Autogel has been shown in the clinical trials to decrease the levels of GH in the majority of patients by >50%, and bring the GH level to the desired level of ≤2.5 ng/mL and decrease IGF-1 to normal levels (adjusted for age) in 40-50% of the patients. The availability of three dose strengths of the drug product allows for adjustment of the dose based on response. However, it is important to be aware that acromegalic patients who are refractory to lanreotide and therefore do not respond to lanreotide treatment will not respond to treatment even with high lanreotide concentrations.
The side effects that occurred most often are similar to those experienced with the administration of natural somatostatin. These tend to be GI side effects, hyperglycemia, cholelithiasis and formation of gallbladder sludge, and bradycardia. In the majority of patients these side effects are tolerable. The only side effects which did not show dose response in the clinical trials were hyperglycemia, cholelithiasis and formation of gallbladder sludge. Somatuline Autogel has been marketed in many countries in Europe and Asia since 2000. The review of the submitted post marketing safety update reports has not shown an increased incidence and severity of the side effects after marketing, nor were there other side effects reported which were not previously experienced under the conditions of the clinical trials. Therefore, the benefit/risk assessment for Somatuline Autogel 60 mg, 90 mg, and 120 mg is considered positive.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Somatuline Autogel is favourable in the treatment of long-term treatment of patients with acromegaly due to pituitary tumours who have had inadequate response to or cannot be treated with surgery and/or radiotherapy, and for the relief of symptoms associated with acromegaly. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Somatuline® Autogel®
| Submission Milestone | Date |
|---|---|
| Submission filed | 2005-05-24 |
| Screening | |
| Screening Deficiency Notice issued | 2005-06-13 |
| Response filed | 2005-07-08 |
| Screening Acceptance Letter issued | 2005-07-22 |
| Review | |
| Clinical Evaluation complete | 2006-05-24 |
| Quality Evaluation complete | 2006-07-05 |
| Labelling Review complete | 2006-05-24 |
| NOC issued by Director General | 2006-07-17 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SOMATULINE AUTOGEL | 02283395 | IPSEN BIOPHARMACEUTICALS CANADA INC | LANREOTIDE (LANREOTIDE ACETATE) 60 MG / SYR |
| SOMATULINE AUTOGEL | 02283417 | IPSEN BIOPHARMACEUTICALS CANADA INC | LANREOTIDE (LANREOTIDE ACETATE) 120 MG / SYR |
| SOMATULINE AUTOGEL | 02283409 | IPSEN BIOPHARMACEUTICALS CANADA INC | LANREOTIDE (LANREOTIDE ACETATE) 90 MG / SYR |