1Sandostatin LAR® Depot (octreotide acetate for injectable suspension)Caution: Federal law prohibits dispensing without a prescription.DESCRIPTIONOctreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic propertiesmimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2fi7)-disulfide; [R-(R*,R*)].Sandostatin LAR® Depot is available in a vial containing the sterile drug product, which when mixed with diluent,becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributedwithin the microspheres which are made of a biodegradeable glucose star polymer, D,L-lactic and glycolic acidscopolymer. Sterile mannitol is added to the microspheres to improve suspendability.Sandostatin LAR® Depot is available as: sterile 5 mL vials in 3 strengths delivering 10 mg, 20 mg or 30 mgoctreotide free peptide. Each vial of Sandostatin LAR® Depot delivers:Name Of Ingredient10 mg20 mg30 mgOctreotide acetate11.2 mg*22.4 mg*33.6 mg*D,L-lactic and glycolic acidscopolymer188.8 mg377.6 mg566.4 mgMannitol41.0 mg81.9 mg122.9 mg*Equivalent to 10/20/30 mg octreotide base.Each vial of diluent contains:carboxymethylcellulose sodium10.0 mgmannitol12.0 mgwater for injection 2.0 mLThe molecular weight of octreotide is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is:H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-o1·xCH3COOHwhere x = 1.4 to 2.5CLINICAL PHARMACOLOGYSandostatin LAR® Depot is a long-acting dosage form consisting of microspheres of the biodegradable glucosestar polymer, D,L-lactic and glycolic acids copolymer, containing octreotide. It maintains all of the clinical andpharmacological characteristics of the immediate-release dosage form Sandostatin® (octreotide acetate) Injectionwith the added feature of slow release of octreotide from the site of injection, reducing the need for frequentadministration. This slow release occurs as the polymer biodegrades, primarily through hydrolysis. SandostatinLAR® Depot is designed to be injected intramuscularly (intragluteally) once every four weeks.Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potentinhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LHresponse to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinalpeptide, secretin, motilin, and pancreatic polypeptide.
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`2By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated withmetastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas(watery diarrhea)Octreotide substantially reduces and in many cases can normalize growth hormone and/or IGF-I (somatomedin C)levels in patients with acromegaly.Single doses of Sandostatin® Injection given subcutaneously have been shown to inhibit gallbladder contractilityand to decrease bile secretion in normal volunteers. In controlled clinical trials the incidence of gallstone or biliarysludge formation was markedly increased (See WARNINGS).Octreotide may cause clinically significant suppression of thyroid stimulating hormone (TSH).PharmacokineticsThe magnitude and duration of octreotide serum concentrations after an intramuscular injection of the long actingdepot formulation Sandostatin LAR(cid:210) Depot reflect the release of drug from the microsphere polymer matrix.Drug release is governed by the slow biodegradation of the microspheres in the muscle, but once present in thesystemic circulation, octreotide distributes and is eliminated according to its known pharmacokinetic propertieswhich are as follows:1. Pharmacokinetics of octreotide acetateAccording to data obtained with the immediate release formulation, Sandostatin(cid:210) Injection solution, aftersubcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrationsof 5.2 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenousand subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve values weredose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of200 mcg t.i.d. (600 mcg/day). Clearance was reduced by about 66% suggesting non-linear kinetics of the drug atdaily doses of 600 mcg/day as compared to 150 mcg/day. The relative decrease in clearance with doses above600 mcg/day is not defined.In healthy volunteers the distribution of octreotide from plasma was rapid (ta½ = 0.2 h), the volume of distribution(Vdss) was estimated to be 13.6 L and the total body clearance was 10 L/h.In blood, the distribution of octreotide into the erythrocytes was found to be negligible and about 65% was bound inthe plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, toalbumin.The elimination of octreotide from plasma had an apparent half-life of 1.7 hours, compared with the 1-3 minuteswith the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin®Injection solution is variable but extends up to 12 hours depending upon the type of tumor, necessitating multipledaily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchanged into theurine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life(46%) and a significant decrease in the clearance (26%) of the drug.In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peakconcentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume ofdistribution (Vdss) was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. Themean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in healthysubjects (from approximately 10 L/h to 4.5 L/h).The effect of hepatic diseases on the disposition of octreotide is unknown.2. Pharmacokinetics of Sandostatin LAR® DepotAfter a single i.m. injection of the long acting depot dosage form Sandostatin LAR® Depot in healthy volunteersubjects, the serum octreotide concentration reached a transient initial peak of about 0.03 ng/mL/mg within 1 hour
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`Exhibit 1060
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`2after administration progressively declining over the following 3 to 5 days to a nadir of <0.01 ng/mL/mg, thenslowly increasing and reaching a plateau about two to three weeks post injection. Plateau concentrations weremaintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about0.07 ng/mL/mg. After about 6 weeks post injection, octreotide concentration slowly decreased, to <0.01 ng/mL/mgby weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. Therelative bioavailability of the long-acting release Sandostatin LAR® Depot compared to immediate-releaseSandostatin® Injection solution given subcutaneously was 60 - 63%.In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 30 mgSandostatin LAR® Depot were dose proportional. The transient day 1 peak, amounting to 0.3 ng/mL, 0.8 ng/mL,and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 ng/mL, 1.3 ng/mL, and 2.0 ng/mL,respectively, achieved about 3 weeks post injection. These plateau concentrations were maintained for nearly 2weeks.Following multiple doses of Sandostatin LAR® Depot given every 4 weeks, steady-state octreotide serumconcentrations were achieved after the third injection. Concentrations were dose proportional and higher by afactor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotideconcentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 ng/mL, respectively,at peak with 20 mg and 30 mg Sandostatin LAR® Depot given every 4 weeks. No accumulation of octreotidebeyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injectionsof Sandostatin LAR® Depot. With the long-acting depot formulation Sandostatin LAR® Depot administered i.m.every 4 weeks the peak-to-trough variation in octreotide concentrations ranged from 44% to 68%, compared to the163% to 209% variation encountered with the daily subcutaneous t.i.d. regimen of Sandostatin® Injection solution.In patients with carcinoid tumors, the mean octreotide concentrations after 6 doses of 10 mg, 20 mg, and 30 mgSandostatin LAR® Depot administered by i.m. injection every four weeks were 1.2 ng/mL, 2.5 ng/mL, and4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after2 injections of 20 and 30 mg and after three injections of 10 mg.Sandostatin LAR® Depot has not been studied in patients with renal impairment.Sandostatin LAR® Depot has not been studied in patients with hepatic impairment.CLINICAL TRIALSThe clinical trials of Sandostatin LAR® Depot were performed in patients who had been receiving Sandostatin®Injection for a period of weeks to as long as 10 years. The acromegaly studies with Sandostatin LAR® Depotdescribed below were performed in patients who achieved GH levels of < 10 ng/mL (and, in most cases < 5 ng/mL)while on subcutaneous Sandostatin® Injection. However, some patients enrolled were partial responders tosubcutaneous Sandostatin(cid:210) Injection, i.e. GH levels were reduced by >50% on subcutaneous Sandostatin®Injection compared to the untreated state, although not suppressed to <5 ng/mL.AcromegalySandostatin LAR(cid:210) Depot was evaluated in three clinical trials in acromegalic patients.In two of the clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level < 5ng/mL on Sandostatin® Injection given in doses of 100 mcg or 200 mcg t.i.d. Most patients were switched to 20mg or 30 mg doses of Sandostatin LAR® Depot given once every 4 weeks for up to 27 to 28 injections. A fewpatients received doses of 10 mg and a few required doses of 40 mg. GH and IGF-I levels were at least as well-controlled with Sandostatin LAR® Depot as they had been on Sandostatin® Injection and this level of controlremained for the entire duration of the trials.A third trial was a 12-month study that enrolled 151 patients who had a GH level < 10 ng/mL after treatment withSandostatin® Injection (most had levels < 5 ng/mL). The starting dose of Sandostatin LAR(cid:210) Depot was 20 mgevery 4 weeks for 3 doses. Thereafter, patients received 10, 20 or 30 mg every 4 weeks, depending upon the degreeof GH suppression. (The recommended regimen for these dosage changes is described under Dosage and
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`3Administration). GH and IGF-I were at least as well-controlled on Sandostatin LAR® Depot as they had been onSandostatin® Injection.Table 1 summarizes the data on hormonal control (GH and IGF-I) for those patients in the first two clinical trialswho received all 27-28 injections of Sandostatin LAR® Depot.
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`Exhibit 1060
`Page 004
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`4Table 1Hormonal Response in Acromegalic Patients Receiving 27-28 Injections During1 Treatment with SandostatinLAR (cid:210)(cid:210) DepotSandostatin(cid:210)Injection S.C.Sandostatin LAR(cid:210) DepotMean Hormone LevelN%N%GH < 5.0 ng/mL69/887873/8883 < 2.5 ng/mL44/885041/8847 < 1.0 ng/mL6/88710/8811IGF-I normalized36/884145/8851GH < 5.0 ng/mL + IGF-I normalized36/884145/8851 < 2.5 ng/mL + IGF-I normalized30/883437/8842 < 1.0 ng/mL + IGF-I normalized5/88610/88111 Average of monthly levels of GH and IGF-I over the course of the trialsFor the 88 patients in Table 1, a mean GH level of < 2.5 ng/mL was observed in 47% receiving Sandostatin LAR®Depot. Over the course of the trials 42% of patients maintained mean growth hormone levels of <2.5 ng/mL andmean normal IGF-I levels.Table 2 summarizes the data on hormonal control (GH and IGF-I) for those patients in the third clinical trial whoreceived all 12 injections of Sandostatin LAR® Depot.Table 2Hormonal Response in Acromegalic Patients Receiving 12 Injections During1 Treatment with SandostatinLAR (cid:210)(cid:210) DepotSandostatin(cid:210)Injection S.C.Sandostatin LAR(cid:210)DepotMean Hormone LevelN%N%GH < 5.0 ng/mL116/12295118/12297 < 2.5 ng/mL84/1226980/12266 < 1.0 ng/mL25/1222128/12223IGF-I normalized82/1226782/12267GH < 5.0 ng/mL + IGF-I normalized80/1226682/12267 < 2.5 ng/mL + IGF-I normalized65/1225370/12257 < 1.0 ng/mL + IGF-I normalized23/1221927/122221 Average of monthly levels of GH and IGF-I over the course of the trial
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`Exhibit 1060
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`5For the 122 patients in Table 2, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mLwas observed in 66% receiving Sandostatin LAR® Depot. Over the course of the trial 57% of patients maintainedmean growth hormone levels of <2.5 ng/mL and mean normal IGF-I levels. In comparing the hormonal responsein these trials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL onsubcutaneous Sandostatin® Injection, 95%, compared to 78% across the two previous trials.In all three trials, GH, IGF-I, and clinical symptoms were similarly controlled on Sandostatin LAR® Depot as theyhad been on Sandostatin® Injection.Of the 25 patients who completed the trials and were partial responders to Sandostatin(cid:210) Injection (GH >5.0ng/mL but reduced by to >50% relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR(cid:210) Depotwith a reduction of GH to <2.5 ng/mL and 8 patients (32%) responded with a reduction of GH to <5.0 ng/mL.Carcinoid SyndromeA 6 month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously beenshown to be responsive to Sandostatin® Injection. Sixty-seven 67 patients were randomized at baseline to receive,double-blind, doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR® Depot every 28 days and 26 patients continued,unblinded, on their previous Sandostatin® Injection regimen (100 to 300 mcg t.i.d.).In any given month after steady-state levels of octreotide were reached, approximately 35% to 40% of the patientswho received Sandostatin LAR® Depot required supplemental subcutaneous Sandostatin(cid:210) Injection therapyusually for a few days, to control exacerbation of carcinoid symptoms. In any given month the percentage ofpatients randomized to subcutaneous Sandostatin(cid:210) Injection, who require supplemental treatment with anincreased dose of Sandostatin(cid:210) Injection, was similar to the percentage of patients randomized to SandostatinLAR(cid:210) Depot. Over the six month treatment period patients who completed the trial on Sandostatin LAR(cid:210)Depot, approximately 50-70% required subcutaneous Sandostatin® Injection supplemental rescue therapy tocontrol exacerbation of carcinoid symptoms although steady state serum Sandostatin LAR(cid:210) Depot levels had beenreached.Table 3 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.
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`Exhibit 1060
`Page 006
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`6Table 3Average No. of Daily Stools and Flushing Episodesin Patients with Malignant Carcinoid SyndromeDaily Stools(Average No.)Daily FlushingEpisodes(Average No.)NBaselineLast VisitBaselineLast VisitSandostatin(cid:210)Injection S.C.263.72.63.00.5SandostatinLAR(cid:210) Depot10 mg224.62.83.00.920 mg204.02.15.90.630 mg244.92.86.11.0Overall, mean daily stool frequency was as well-controlled on Sandostatin LAR® Depot as on Sandostatin®Injection (approximately 2 to 2.5 stools/day).Mean daily flushing episodes were similar at all doses of Sandostatin LAR® Depot and on Sandostatin® Injection(approximately 0.5 to 1 episode/day).In a subset of patients with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole aceticacid) levels were reduced by 38-50% in the groups randomized to Sandostatin LAR(cid:210) Depot.The reductions are within the range reported in the published literature for patients treated with octreotide (about10-50%).Seventy-eight patients with malignant carcinoid syndrome who had participated in this 6 month trial, subsequentlyparticipated in a 12 month extension study in which they received 12 injections of Sandostatin LAR® Depot at4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled asduring the 6 month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional22% of patients prematurely discontinued Sandostatin LAR(cid:210) Depot due to disease progression or worsening ofcarcinoid symptoms.INDICATIONS AND USAGEAcromegalySandostatin LAR® Depot is indicated for long term maintenance therapy in acromegalic patients for whommedical treatment is appropriate and who have been shown to respond to and can tolerate Sandostatin® Injection.The goal of treatment in acromegaly is to reduce GH and IGF levels to normal. Sandostatin LAR® Depot can beused in patients who have had an inadequate response to surgery or in those for whom surgical resection is not anoption. It may also be used in patients who have received radiation and have had an inadequate therapeuticresponse (See Clinical Studies and Dosage and Administration).
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`7Carcinoid TumorsSandostatin LAR® Depot is indicated for long-term treatment of the severe diarrhea and flushing episodesassociated with metastatic carcinoid tumors in patients in whom initial treatment with Sandostatin® Injection hasbeen shown to be effective and tolerated.Vasoactive Intestinal Peptide Tumors (VIPomas)Sandostatin LAR® Depot is indicated for long-term treatment of the profuse watery diarrhea associated withVIP-secreting tumors in patients in whom initial treatment with Sandostatin® Injection has been shown to beeffective and tolerated.In patients with acromegaly, carcinoid syndrome and VIPomas, the effect of Sandostatin(cid:210) Injection andSandostatin LAR(cid:210) Depot on tumor size, rate of growth and development of metastases, has not been determined.CONTRAINDICATIONSSensitivity to this drug or any of its components.WARNINGSAdverse events that have been reported in patients receiving Sandostatin(cid:210) Injection can also be expected inpatients receiving Sandostatin LAR(cid:210) Depot. Incidence figures in the WARNINGS and ADVERSEREACTIONS sections, below, are those obtained in clinical trials of Sandostatin (cid:210) Injection and Sandostatin LAR(cid:210) Depot.Gallbladder and Related EventsSingle doses of Sandostatin® Injection have been shown to inhibit gallbladder contractility and decrease bilesecretion in normal volunteers. In clinical trials with Sandostatin(cid:210) Injection (primarily patients with acromegalyor psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge inpatients who received Sandostatin(cid:210) Injection for 12 months or longer was 52%. The incidence of gallbladderabnormalities did not appear to be related to age, sex or dose but was related to duration of exposure.In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR® Depot for 12 months orlonger, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge and dilatation.The incidence of new cholelithiasis was 22%, of which 7% were microstones.In clinical trials 62% of malignant carcinoid patients who received Sandostatin LAR(cid:210) Depot for up to 18 monthsdeveloped new biliary abnormalities including gallstones, sludge and dilatation. New gallstones occurred in a totalof 24% of patients.Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatichepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascendingcholangitis during Sandostatin® Injection therapy and died. Despite the high incidence of new gallstones inpatients receiving octreotide, 1% patients developed acute symptoms requiring cholecystectomy.PRECAUTIONS (see Adverse Reactions)GeneralGH-secreting tumors may sometimes expand and cause serious complications (e.g., visual field defects).Therefore, all patients with these tumors should be carefully monitored.Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone,which may result in hypoglycemia or hyperglycemia. Octreotide also suppresses secretion of thyroid stimulating
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`8hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred duringtreatment with octreotide.Glucose MetabolismThe hypoglycemia or hyperglycemia which occurs during octreotide therapy is usually mild, but may result in overtdiabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Severe hyperglycemia,subsequent pneumonia, and death following initiation of Sandostatin® Injection therapy was reported in onepatient with no history of hyperglycemia (see Adverse Reactions).Thyroid FunctionHypothyroidism has been reported in acromegaly and carcinoid patients receiving octreotide therapy. Baseline andperiodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotidetherapy (see Adverse Reactions).Cardiac FunctionIn both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities havebeen reported during octreotide therapy. Other EKG changes were observed such as QT prolongation, axis shifts,early repolarization, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes.The relationship of these events to octreotide acetate is not established because many of these patients haveunderlying cardiac disease (see Precautions). Dose adjustments in drugs such as beta-blockers that havebradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation ofSandostatin® Injection therapy resulted in worsening of CHF with improvement when drug was discontinued.Confirmation of a drug effect was obtained with a positive rechallenge (see Adverse Reactions).NutritionOctreotide may alter absorption of dietary fats in some patients.Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients receivingoctreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR®Depot.Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. tract in patients withconditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc mayrise excessively when the fluid loss is reversed. Patients onTPN and octreotide should have periodic monitoring of zinc levels.Information for PatientsPatients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits forreinjection in order to minimize exacerbation of symptoms.Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady controlof GH and IGF-I levels.Laboratory TestsLaboratory tests that may be helpful as biochemical markers in determining and following patient response dependon the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoringthe progress of therapy:Acromegaly:Growth Hormone, IGF-I (somatomedin C)Responsiveness to octreotide may be evaluated by determining growth hormone levels at 1-4 hourintervals for 8-12 hours after subcutaneous injection of Sandostatin® Injection (not SandostatinLAR® Depot). Alternatively, a single measurement of IGF-I (somatomedin C) level may bemade two weeks after initiation of Sandostatin® Injection or dosage change. After patients are
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`9switched from Sandostatin® Injection to Sandostatin LAR® Depot, GH and IGF-Ideterminations may be made after 3 monthly-injections of Sandostatin LAR® Depot. (Steadystate serum levels of octreotide are reached only after a period of 3 months of monthly injections.)GH can be determined using the mean of 4 assays taken at 1 hour intervals. IGF-I can bedetermined with a single assay. All GH and IGF-I determinations should be made 4 weeks afterthe previous Sandostatin LAR® Depot.Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance PVIPoma: VIP (plasma vasoactive intestinal peptide)Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (seePRECAUTIONS — General).Drug InteractionsOctreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption oforally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decreaseblood levels of cyclosporine and result in transplant rejection.Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to controlfluid and electrolyte balance, may require dose adjustments of these therapeutic agents.Drug Laboratory Test InteractionsNo known interference exists with clinical laboratory tests, including amine or peptide determinations.Carcinogenesis/Mutagenesis/Impairment of FertilityStudies in laboratory animals have demonstrated no mutagenic potential of Sandostatin®. No mutagenic potentialof the polymeric carrier in Sandostatin LAR® Depot, (D,L-lactic and glycolic acids copolymer), was observed inthe Ames mutagenicity test.No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks atdoses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneousstudy in rats administered octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cellcarcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x thehuman exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle control groups.The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity ofthe rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritationin humans. There have been no reports of injection site tumors in patients treated with Sandostatin® Injection forat least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day femalescompared to 7% in the saline control females and 0% in the vehicle control females. The presence of endometritiscoupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterinedilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats whichdoes not occur in humans.Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposurebased on body surface area.Pregnancy Category BReproduction studies have been performed in rats and rabbits at doses up to 16 times the highest human dose basedon body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to octreotide.There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductionstudies are not always predictive of human response, this drug should be used during pregnancy only if clearlyneeded.
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`Exhibit 1060
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`10Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in milk, cautionshould be exercised when Sandostatin LAR® Depot is administered to a nursing woman.Pediatric UseSandostatin LAR® Depot has not been studied in pediatric patients.Experience with Sandostatin® Injection in the pediatric population is limited. Its use has been primarily in patientswith congenital hyperinsulinism (also called nesidioblastosis). The youngest patient to receive the drug was 1month old. At doses of 1-40 mcg/kg body weight/day, the majority of side effects observed were gastrointestinal-steatorrhea, diarrhea, vomiting and abdominal distension. Poor growth has been reported in several patients treatedwith Sandostatin(cid:210) Injection for more than 1 year; catch-up growth occurred after Sandostatin® Injection wasdiscontinued. A 16 month old male with enterocutaneous fistula developed sudden abdominal pain and increasednasogastric drainage and died 8 hours after receiving a single 100 mcg subcutaneous dose of Sandostatin®Injection.ADVERSE REACTIONS (see Warnings and Precautions)Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronicoctreotide therapy (See WARNINGS). Few patients, however, develop acute symptoms requiring cholecystectomy.CardiacIn acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% andarrhythmias developed in 9% of patients during Sandostatin® Injection therapy. Electrocardiograms wereperformed only in carcinoid patients receiving Sandostatin LAR(cid:210) Depot. In carcinoid syndrome patients sinusbradycardia developed in 19%; conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. Therelationship of these events to octreotide acetate is not established because many of theses patients have underlyingcardiac disease (see Precautions).GastrointestinalThe most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptomsin clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 4.Table 4Number (%) of Acromegalic Patients with Common G.I. Adverse EventsEventSandostatin®Injection S.C.t.i.dn = 114Sandostatin LAR(cid:210) Depotq. 28 daysn = 261N%N%
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`Exhibit 1060
`Page 011
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`11DiarrheaAbdominal Painor DiscomfortFlatulenceConstipationNauseaVomiting66501510345(57.9)(43.9)(13.2)(8.8)(29.8)(4.4)957667492717(36.4)(29.1)(25.7)(18.8)(10.3)(6.5)Only 2.6% of the patients on Sandostatin® Injection in U.S. clinical trials discontinued therapy due to thesesymptoms. No acromegalic patient receiving Sandostatin LAR® Depot discontinued therapy for a G.I. event.In patients receiving Sandostatin LAR® Depot the incidence of diarrhea was dose-related. Diarrhea, abdominalpain, and nausea developed primarily during the first month of treatment with Sandostatin LAR® Depot.Thereafter, new cases of these events were uncommon The vast majority of these events were mild to moderate inseverity.In rare instances gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressiveabdominal distention, severe epigastric pain, abdominal tenderness, and guarding.Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4% to 6% of patients.In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27% to 38% andconstipation or vomiting in 15% to 21% of patients treated with Sandostatin LAR® Depot. Diarrhea was reportedas an adverse event in only 14% of patients but since most of the patients had diarrhea as a symptom of carcinoidsyndrome, it is difficult to assess the actual incidence of drug-related diarrhea.Hypo/HyperglycemiaIn acromegaly patients treated with either Sandostatin® Injection or Sandostatin LAR(cid:210) Depot, hypoglycemiaoccurred in approximately 2% and hyperglycemia in approximately 15% of patients. In carcinoid patients,hypoglycemia occurred in 4 % and hyperglycemia in 27% of p