SOMATULINE L.P

Injection 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL is a prolonged-release formulation for deep subcutaneous injection.

It contains the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, water for injection and acetic acid (for pH adjustment).

Injection is available as sterile, ready-to-use, single-dose prefilled syringes containing lanreotide acetate supersaturated bulk solution of 24.6% w/w lanreotide base.

Each syringe contains

Lanreotide Injection 60 mg/0.2 mL Lanreotide Injection 90 mg/0.3 mL Lanreotide Injection 120 mg/0.5 mL Lanreotide acetate 89.9 mg 123.2 mg 156.6 mg Acetic Acid q.s. q.s. q.s.

Water for injection 236.4 mg 324.1 mg 411.6 mg Total Weight 328.9 mg 450.9 mg 572.8 mg Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin.

Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D­ alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt.

Its molecular weight is 1096.34 (base) and its amino acid sequence is: The Lanreotide Injection in the prefilled syringe is a white to pale yellow, semi-solid formulation.

Injection is a somatostatin analog indicated for: the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. the treatment of adult patients with unresectable, well.

• or moderately.

• differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy. 1.1 Acromegaly Lanreotide Injection is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.

The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal. 1.2 Gastroenteropancreatic Neuroendocrine Tumors Lanreotide Injection is indicated for the treatment of adult patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. 1.3 Carcinoid Syndrome Lanreotide Injection is indicated for the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy.

Acromegaly Lactation Cardiopathies Insulin-necessary diabetes Pregnancy

Subject under 18 Extended treatment.

Lanreotide, the active component of Lanreotide Injection, is an octapeptide analog of natural somatostatin.

The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin. 12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and and a reduced binding affinity for human SSTR1, 3, and 4.

Activity at human

SSTR2 and is the primary mechanism believed responsible for GH inhibition.

Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions.

The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients.

In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way.

After a single injection of lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days.

In Study 4, patients with carcinoid syndrome treated with lanreotide injection 120 mg every 4 weeks had reduced levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) compared with placebo.

Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin.

Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK).

In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance.

Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.

Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects.

In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow but has no effect on basal or meal-stimulated renal blood flow.

Lanreotide has no effect on renal plasma flow or renal vascular resistance.

However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.

In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration.

In diabetic non-acromegalic subjects receiving a continuous infusion (21-day) of lanreotide, serum glucose concentrations were temporarily decreased by 20% to 30% after the start and end of the infusion.

Serum glucose concentrations returned to normal levels within 24 hours.

A significant decrease in insulin concentrations was recorded between baseline and Day 1 only.

Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects.

Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis. 12.3 Pharmacokinetics Lanreotide Injection is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids.

The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream.

After a single, deep subcutaneous administration, the mean absolute bioavailability of lanreotide in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively.

Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax and showed high inter-subject variability.

Lanreotide showed sustained release of lanreotide with a half-life of to 30 days.

Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion.

In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration.

At doses of lanreotide between and 120 mg, linear pharmacokinetics were observed in acromegalic patients.

At steady state, mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7, and 7.7 ± 2.5 ng/mL, increasing linearly with dose.

The mean accumulation ratio index was 2.7, which is in line with the range of values for the half-life of lanreotide.

The steady.

• state trough serum lanreotide concentrations in patients receiving lanreotide every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60 mg, 90 mg, and 120 mg doses, respectively.

A limited initial burst effect and a low peak-to-trough fluctuation (81% to 108%) of the serum concentration at the plateau were observed.

For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1, and 4.0 ± 1.4 ng/mL, respectively).

Pharmacokinetic data from studies evaluating extended dosing use of lanreotide injection 120 mg demonstrated mean steady-state, Cmin values between 1.6 and 2.3 ng/mL for the 8.

• and 6-week treatment interval, respectively.

Gastroenteropancreatic Neuroendocrine Tumors In patients with

GEP-NETs treated with lanreotide 120 mg every 4 weeks, steady state concentrations were reached after to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL.

Injection has not been studied in specific populations.

However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose.

Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects.

Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged to 85 years with neuroendocrine tumors.

An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2­fold increase in half-life and AUC was observed.

Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with lanreotide.

GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied.

In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed.

The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of Lanreotide Injection or of other lanreotide products.

Laboratory investigations of acromegalic patients treated with lanreotide injection in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (less than 1% to 4% of patients in specific studies whose antibodies were tested).

The antibodies did not appear to affect the efficacy or safety of lanreotide injection.

Study 3, development of anti-lanreotide antibodies was assessed using a radioimmunoprecipitation assay.

In patients with

GEP-NETs receiving lanreotide injection, the incidence of anti-lanreotide antibodies was 4% (3 of 82) at 24 weeks, 10% (7 of 67) at 48 weeks, 11% (6 of 57) at 72 weeks, and 10% (8 of 84) at 96 weeks.

Assessment for neutralizing antibodies was not conducted.

Study 4, less than 2% (2 of 108) of the patients treated with lanreotide injection developed anti-lanreotide antibodies.

Mechanism of action

Lanreotide is a natural somatostatin-like octapeptide.

As somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrines, exocrines and paracrine functions.

It has a high affinity for human somatostatin receptors (SSTR) 2 and 5, and a low affinity for SSTR and 4.

Inhibition of growth hormone would be mainly explained by this activity at SSTR and 5.

Lanreotide is more active than natural somatostatin and has a longer duration of action.

It is characterized by a marked selectivity vis-à-vis the secretion of growth hormone, the enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme-like enzyme.

• Alkaline phosphates (increase) (Uncommon)
• ALT (increase) (Common)
• Hyperbilirubinaemia (Common)
• ASAT (increase) (Uncommon)
• Hemoglobin glycosylated (increase) (Common)
• Hyponatremia (Uncommon)
• Hyperglycaemia (Common)
• Pancreatic enzymes (decrease) (Common)
• Hypoglycaemia (Common)
• Alopecia (Common)
• Hypotrithythmia (Common)
• Asthenia (Common)
• Fatigue (Common)
• Bile lithiasis (Very common)
• Dilatation of bile tracks (Common)
• Cholecystitis Cholangite Oedema of Quincke Anaphylactic reaction
• Hypersensitivity Angioedema Injection site reaction (Common)
• Nodule at the injection site
• Pruritus at the injection site Abscesses at the injection site Pain at injection site
• Injection site induration Diabetes (Common)
• Weight (decrease) (Common)
• Appetite decreased (Common)
• Feeling dizzy (Common)
• Lethargy (Common)
• Insomnia (Uncommon)
• Hot flash (Uncommon)
• Sinus bradycardia (Common)
• Abdominal distension (Common)
• Soft stool (Very common)
• Abdominal discomfort (Common)
• Nausea (Common)
• Constipation (Common)
• Vomiting (Common)
• Dyspepsia (Common)
• Diarrhoea (Very common)
• Discoloration of stools (Uncommon)
• Flatulence (Common)
• Abdominal pain (Very common)
• Steatorrhoea (Common)
• Pancreatitis Digestive disorder
• Musculoskeletal pain (Common)
• Muscle pain (Common)
• Headache (Common).

Injection is contraindicated in patients with history of a hypersensitivity to lanreotide.

Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide.

Hypersensitivity to lanreotide.

For deep subcutaneous injection only.

Intended for administration by a healthcare provider.

Administer in the superior external quadrant of the buttock.

Alternate injection sites.

Acromegaly: 90 mg every 4 weeks for 3 months.

Adjust thereafter based on

GH and/or IGF-1 levels.

See full prescribing information for titration regimen.

GEP-NETs: 120 mg every 4 weeks.

Syndrome: 120 mg every 4 weeks.

If patients are already being treated with Lanreotide Injection for GEP-NET, do not administer an additional dose for carcinoid syndrome.

See full prescribing information for dosage adjustment in patients with acromegaly and renal or hepatic impairment. 2.1 Recommended Dosage Acromegaly The recommended starting dosage of Lanreotide Injection is 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months.

After 3 months, the Lanreotide injection dosage may be adjusted as follows: GH greater than 1 ng/mL to less than or equal to 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain dosage at 90 mg every 4 weeks.

GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase dosage to 120 mg every 4 weeks.

GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce dosage to 60 mg every 4 weeks.

Thereafter, the dosage should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly.

Patients who are controlled on Lanreotide

Injection 60 or 90 mg may be considered for an extended dosing interval of Lanreotide Injection 120 mg every 6 or 8 weeks.

GH and

IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response.

Continued monitoring of patient response with dosage adjustments for biochemical and clinical symptom control, as necessary, is recommended.

Tumors (GEP-NETs) The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection.

Carcinoid Syndrome The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection.

If patients are already being treated with Lanreotide Injection for GEP-NETs, do not administer an additional dose for the treatment of carcinoid syndrome. 2.2 Dosage Adjustment in Renal Impairment Acromegaly The recommended starting dosage of Lanreotide Injection in acromegalic patients with moderate or severe renal impairment (creatinine clearance (CLcr) less than 60 mL/min) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment. 2.3 Dosage Adjustment in Hepatic Impairment Acromegaly The recommended starting dosage of Lanreotide Injection in acromegalic patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment. 2.4 Important Preparation and Administration Instructions The following instructions explain how to inject Lanreotide Injection: Read all instructions carefully before starting the injection.

Follow this procedure exactly, as it may differ from your past experience.

This is a single-dose pre-filled syringe with a single-use safety needle with a green needle shield (that cannot be removed) in a clear needle cap.

ALL the medication must be injected

SLOWLY over 20 seconds during the use.

If you drop or damage the device in any way, please call 1-866-604-3268.

Figure The box includes the following items: Sterile needle pack containing Sterile needle Sterile Laminated pouch with sterile syringe pre-filled with LANREOTIDE INJECTION Instructions for Use Leaflet Prescribing Information Leaflet CAUTION NEVER TOUCH OR TRY TO OPEN THE GREEN NEEDLE SHIELD throughout the course of operation of the device.

Green needle shield is

NOT a removable cap or cover for the needle.

Green needle shield will automatically activate once the injection is complete.

Green needle shield is a self-operating safety lock mechanism.

Needle is fully covered by green needle shield.

Needle is visible only through a small window in the green needle shield.

Inject medication slowly over 20 seconds.

DO NOT rush the injection.

Remove box from refrigerator 30 minutes prior to injecting.

Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time.

Stretch out the skin around injection site to make it flat and tight using your thumb and index finger.

DO NOT pinch the skin around injection site.

A. BEFORE YOU START Figure 2 A1.

INJECTION from the refrigerator 30 minutes prior to injecting (Figure 2).

Do not open the sterile pouch yet.

Product left in its sealed pouch at room temperature (not to exceed 104° F or 40 °C) for up to 72 hours may be returned to the refrigerator for continued storage and use at a later time.

Figure 3 A2.

Wash your hands with soap and dry your hands thoroughly before starting (Figure 3).

Follow the doctor or institution’s policy on the use of surgical gloves during the procedure Figure 4 A3.

Before opening the sterile pouch, confirm that it is intact, and that the medication has not expired.

Syringe is sterile only if the pouch is sealed and undamaged.

Do not use if the pouch is opened, tampered with or damaged.

The expiry date is printed on the outer carton and the pouch.

• Do not use if the medication has expired. (Figure 4).

Or Figure 5 A4.

Make sure there is a clean surface for preparation.

Find a clean, comfortable area for the patient to relax during procedure (Figure 5).

It's important that the patient remains as still as possible during the injection.

Figure 6 A5.

Choose injection site.

• the sites are upper outer areas of the buttock as shown below It is very important that you only inject in one of the areas marked OK in the picture (Figure 6).

Alternate the injection site between the right and left side each time an injection of LANREOTIDE INJECTION is administered.

Figure 7 A6.

Prepare the injection site by cleaning it with alcohol wipes (Figure 7) .

Figure 8 A7.

Tear open the sterile pouch and take out the sterile pre-filled syringe (Figure 8).

B. PREPARE THE SYRINGE Figure 9 B1: Open the sterile needle cap (Figure 9) The needle is sterile only if the needle cap is sealed and undamaged.

Do not use if the needle cap is opened, tampered with or damaged.

Hold the clear needle cap and pull the lid off.

DO NOT TOUCH THE OPEN END OF THE NEEDLE CAP TO MAINTAIN STERILITY.

Figure 10 B2: Remove the cap from the sterile syringe (Figure 10) With one hand, hold the syringe barrel steady (not the plunger ).

With the other hand, remove the cap by twisting it.

B3: Prepare the assembly (Figure 11) Figure 11 Hold the needle cap with one hand and the syringe barrel ( not the plunger ) with the other Carefully insert the open end of the syringe into the open end of the needle cap Twist the syringe barrel clockwise until it is tight to make sure that the syringe is well connected to the safety needle.

DEVICE (SYRINGE AND NEEDLE) ARE COMPLETELY CONNECTED.

The assembly is fully locked when you cannot turn it any further.

B4: Remove the needle from the needle cap Figure 12 Hold the syringe barrel ( not the plunger ).

Pull the needle straight out from the needle cap without twisting or turning (Figure 12).

Figure 13 CAUTION: NEVER TOUCH THE GREEN NEEDLE SHIELD.

THERE IS A RISK OF NEEDLE STICK INJURY. (Figure 13) Green needle shield is a self-operating safety lock mechanism and is not a removable cover or cap for the needle.

It will activate once the injection is complete.

The needle is fully covered by the green shield and is visible only through the small round window at the end of the shield.

C.PERFORM INJECTION C1: Position the syringe assembly Figure 14 Stretch out the skin around the injection site to make it flat and tight using your thumb and index finger. (Figure 14) Figure 15 DO NOT pinch the skin (Figure 15) Figure 16 Hold the assembly by the lower part of the syringe barrel ( not the plunger ) with your other hand.

Position the syringe assembly at a 90-degree angle to the skin.

The green collar at the bottom of the green shield should be perpendicular to the injection site (Figures and 17) Figure 17 C2: Insert the needle (Figure 18) Figure 18 Holding the skin flat and tight, push the syringe assembly firmly into the skin.

Do NOT pinch the skin.

Keep pushing until you reach a “hard stop” and only the green collar at the end of the green needle shield remains visible.

Do NOT push the plunger yet.

DO NOT aspirate.

Keep pressing against the skin.

During this step you should not see the needle.

C3: Push the top of the plunger (Figure 19) Figure 19 Keep holding your hand on the syringe barrel to maintain a 90-degree angle throughout the injection.

While keeping the syringe pressed against the skin, slowly press down the plunger.

You may want to use both hands while applying pressure during the injection of drug.

Continue slowly pushing the plunger over 20 seconds until the Plunger top touches the syringe end.

The medication is thicker and harder to push than you might expect.

Pushing the plunger too fast may cause discomfort to the patient.

While depressing the plunger, slowly count to and CONTINUE STEADY PRESSURE on the plunger.

You may find it helpful to say: a “1 one-thousand” b “2 one-thousand” c “3 one-thousand” up to “20 one-thousand” During this step, as the needle is lowering, the green needle shield will retract.

You should only see the green collar of the green needle shield.

D. REMOVE AND THROW AWAY THE SYRINGE ASSEMBLY Figure 20 D1: Remove from the skin (Figure 20) Lift the syringe straight up and away from the body.

The green needle shield will return to its original position and will fully cover the needle.

Figure 21 D2: Apply gentle pressure (Figure 21) Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding.

Do NOT rub or massage the injection site after administration.

Figure 22 D3: Check needle (Figure 22) Check through the green needle shield’s round windows that the needle was not damaged during administration.

If any damage or malfunction to the needle is suspected please contact 1-866-604-3268 Figure 23 D4: Throw away / Disposal (Figure 23) DO NOT remove needle from syringe Dispose of complete product in sharps disposal container Do not dispose of the syringe or needle in the regular trash.

The syringe and needle are not reusable. fig 1 fig 2 fig 3 fig 4 fig 5 fig 6 fig 7 fig 8 fig 9 fig 10 fig 11 fig 12 fig 13 fig 14 fig 15 fig 16 fig 17 fig 18 fig 19 fig 20 fig 21 fig 22 fig 23 fig 24 fig 25 fig 26 fig 27 fig 28 Fig 29.

Injection is supplied in strengths of 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL lanreotide as a white to pale yellow, semi-solid formulation in a single-dose, sterile, prefilled, ready-to-use, polypropylene syringe and a safety needle device.

The safety needle device is a sterile, single use needle system consisting of a needle (1.2 mm x 20 mm, stainless steel) held in protective plastic safety housing.

The single-dose prefilled syringe is contained in a plastic tray and is packed in a triple-layered aluminium pouch.

The sterile safety needle is co-packaged along with the sealed aluminium pouch in the kit carton box and is attached to the former at the point of use.

NDC 69097-880-67 60 mg/0.2 mL lanreotide, sterile, prefilled syringe NDC 69097-890-67 90 mg/0.3 mL lanreotide, sterile, prefilled syringe NDC 69097-870-67 120 mg/0.5 mL lanreotide, sterile, prefilled syringe Storage and Handling Store Lanreotide Injection in the refrigerator at 2°C to 8°C (36°F to 46°F).

Protect from light.

Store in the original package.

Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time.

Limited available data based on post-marketing case reports with lanreotide use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes.

In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5.

• and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively The background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival.

A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities.

The safety and effectiveness of Lanreotide

Injection in pediatric patients have not been established.

No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Studies and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.