Sandostatin LAR® Depot(octreotide acetate for injectable suspension)
`
`Caution: Federal law prohibits dispensing without a prescription.
`
`DESCRIPTION
`
`Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties
`mimicking 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 (2—>7)-disulfide; [R-(R*,R*)].
`
`Sandostatin LAR® Depotis available in a vial containing the sterile drug product, which when mixed with diluent,
`becomesa suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed
`within the microspheres which are made of a biodegradeable glucose star polymer, D,L-lactic and glycolic acids
`copolymer. Sterile mannitol is added to the microspheres to improve suspendability.
`
`Sandostatin LAR® Depotis available as: sterile 5 mL vials in 3 strengths delivering 10 mg, 20 mg or 30 mg
`octreotide free peptide. Each vial of Sandostatin LAR® Depotdelivers:
`
`NameOfIngredient
`
`10 mg
`
`20 mg
`
`30 mg
`
`Octreotide acetate
`
`11.2 mg*
`
`22.4mg*
`
`33.6 mg*
`
`D,L-lactic and glycolic acids
`copolymer
`
`188.8 mg
`
`377.6mg
`
` 566.4mg
`
`Mannitol
`
`41.0 mg
`
`81.9 mg
`
`122.9 mg
`
`*Equivalent to 10/20/30 mg octreotide base.
`
`Eachvial of diluent contains:
`
`carboxymethylcellulose sodium
`
`10.0 mg
`
`mannitol
`
`water for injection
`
`12.0 mg
`
`2.0 mL
`
`The molecular weight of octreotide is 1019.3 (free peptide, C4gHggNi9O10S2) and its amino acid sequenceis:
`
`H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol -xCH;COOH
`
`where x = 1.4 to 2.5
`
`CLINICAL PHARMACOLOGY
`
`Sandostatin LAR® Depotis a long-acting dosage form consisting of microspheres of the biodegradable glucose
`star polymer, D,L-lactic and glycolic acids copolymer, containing octreotide. It maintainsall of the clinical and
`pharmacological characteristics of the immediate-release dosage form Sandostatin® (octreotide acetate) Injection
`with the added feature of slow release of octreotide from the site of injection, reducing the need for frequent
`administration. This slow release occurs as the polymer biodegrades, primarily through hydrolysis. Sandostatin
`LAR® Depotis 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 potent
`inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH
`response to GnRH,decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal
`peptide, secretin, motilin, and pancreatic polypeptide.
`
`West-Ward Pharm.
`Exhibit 1060
`Page 001
`
`West-Ward Pharm.
`Exhibit 1060
`Page 001
`
`

`

`2
`
`Byvirtue of these pharmacological actions, octreotide has been usedto treat the symptoms associated with
`metastatic 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 contractility
`and to decrease bile secretion in normal volunteers. In controlled clinicaltrials the incidence of gallstone or biliary
`sludge formation was markedly increased (See WARNINGS).
`
`Octreotide may causeclinically significant suppression of thyroid stimulating hormone (TSH).
`
`Pharmacokinetics
`
`The magnitude and duration of octreotide serum concentrations after an intramuscular injection of the long acting
`depot formulation Sandostatin LAR® Depotreflect 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 the
`systemic circulation, octreotide distributes and is eliminated according to its known pharmacokinetic properties
`whichare as follows:
`
`1. Pharmacokinetics of octreotide acetate
`
`According to data obtained with the immediate release formulation, Sandostatin® Injection solution,after
`subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations
`of 5.2 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous
`and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve values were
`dose proportional both after subcutaneousor intravenoussingle doses up to 400 mcg and with multiple doses of
`200 mcg t.i.d. (600 mcg/day). Clearance was reduced by about 66% suggesting non-linear kinetics of the drug at
`daily doses of 600 mcg/day as compared to 150 mcg/day. Therelative decrease in clearance with doses above
`600 mcg/dayis not defined.
`
`In healthy volunteers the distribution of octreotide from plasma wasrapid (tOy, = 0.2 h), the volumeofdistribution
`(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 in
`the plasmain a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to
`albumin.
`
`The elimination of octreotide from plasma had an apparenthalf-life of 1.7 hours, compared with the 1-3 minutes
`with the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin®
`Injection solution is variable but extends up to 12 hours depending uponthe type of tumor, necessitating multiple
`daily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchangedinto the
`urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life
`(46%) anda significant decrease in the clearance (26%) of the drug.
`
`In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak
`concentration of 2.8 ng/mL (100 mcg dose) was reachedin 0.7 hours after subcutaneous dosing. The volume of
`distribution (Vdss) was estimated to be 21.6 + 8.5 L andthe total body clearance wasincreased to 18 L/h. The
`mean 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 healthy
`subjects (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® Depot
`
`After a single i.m. injection of the long acting depot dosage form Sandostatin LAR® Depotin healthy volunteer
`subjects, the serum octreotide concentration reached a transientinitial peak of about 0.03 ng/mL/mg within 1 hour
`
`West-Ward Pharm.
`Exhibit 1060
`Page 002
`
`West-Ward Pharm.
`Exhibit 1060
`Page 002
`
`

`

`2
`
`after administration progressively declining over the following 3 to 5 days to a nadir of <0.01 ng/mL/mg, then
`slowly increasing and reaching a plateau about two to three weeks post injection. Plateau concentrations were
`maintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about
`0.07 ng/mL/mg. After about 6 weeks post injection, octreotide concentration slowly decreased,
`to <0.01 ng/mL/mg
`by weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. The
`relative bioavailability of the long-acting release Sandostatin LAR® Depot compared to immediate-release
`Sandostatin® Injection solution given subcutaneously was 60 - 63%.
`
`In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 30 mg
`Sandostatin 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 weekspost injection. These plateau concentrations were maintained for nearly 2
`weeks.
`
`Following multiple doses of Sandostatin LAR® Depot given every 4 weeks, steady-state octreotide serum
`concentrations were achieved after the third injection. Concentrations were dose proportional and higher by a
`factor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotide
`concentrations 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® Depotgiven every 4 weeks. No accumulation of octreotide
`beyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injections
`of 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 the
`163% to 209% variation encountered with the daily subcutaneoust.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 mg
`Sandostatin LAR® Depot administered by i.m. injection every four weeks were 1.2 ng/mL, 2.5 ng/mL, and
`4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after
`2 injections of 20 and 30 mg andafter three injections of 10 mg.
`
`Sandostatin LAR® Depothas not been studied in patients with renal impairment.
`
`Sandostatin LAR® Depothas not been studied in patients with hepatic impairment.
`
`CLINICAL TRIALS
`
`Theclinical 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® Depot
`described 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, somepatients enrolled were partial responders to
`subcutaneous Sandostatin® 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.
`
`Acromegaly
`
`Sandostatin LAR® Depot was evaluated in three clinicaltrials in acromegalic patients.
`
`In two ofthe clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level < 5
`ng/mL on Sandostatin® Injection given in doses of 100 mcg or 200 mcg t.i.d. Most patients were switched to 20
`mg or 30 mg doses of Sandostatin LAR® Depot given once every 4 weeks for up to 27 to 28 injections. A few
`patients 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® Depotas they had been on Sandostatin® Injection andthis level of control
`remained for the entire duration ofthetrials.
`
`A third trial was a 12-month study that enrolled 151 patients who had a GH level < 10 ng/mLafter treatment with
`Sandostatin® Injection (most had levels < 5 ng/mL). Thestarting dose of Sandostatin LAR® Depot was 20 mg
`every 4 weeks for 3 doses. Thereafter, patients received 10, 20 or 30 mg every 4 weeks, depending upon the degree
`of GH suppression. (The recommended regimen for these dosage changes is described under Dosage and
`
`West-Ward Pharm.
`Exhibit 1060
`Page 003
`
`West-Ward Pharm.
`Exhibit 1060
`Page 003
`
`

`

`Administration). GH and IGF-I were at least as well-controlled on Sandostatin LAR® Depot as they had been on
`Sandostatin® Injection.
`
`Table 1 summarizes the data on hormonal control (GH and IGF-I) for those patients in the first two clinical trials
`whoreceived all 27-28 injections of Sandostatin LAR® Depot.
`
`3
`
`West-Ward Pharm.
`Exhibit 1060
`Page 004
`
`West-Ward Pharm.
`Exhibit 1060
`Page 004
`
`

`

`Table 1
`
`HormonalResponse in Acromegalic Patients Receiving 27-28 Injections During’ Treatment with Sandostatin
`LAR® Depot
`
` Sandostatin LAR® Depot
`
`Sandostatin®
`Injection S.C.
`
`Mean Hormone Level
`
`N
`
`%
`
`GH < 5.0 ng/mL
`
`< 2.5 ng/mL
`
`< 1.0 ng/mL
`
`IGF-I normalized
`
`41
`
`GH < 5.0 ng/mL + IGF-I
`normalized
`
`< 2.5 ng/mL + IGF-I
`normalized
`
`< 1.0 ng/mL +IGF-I
`normalized
`
`N
`
`73/88
`
`41/88
`
`10/88
`
`45/88
`
`45/88
`
`37/88
`
`10/88
`
`%
`
`83
`
`47
`
`11
`
`51
`
`51
`
`42
`
`11
`
`' Average of monthly levels of GH and IGF-I over the course ofthe trials
`
`For 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 hormonelevels of <2.5 ng/mL and
`mean normal IGF-I levels.
`
`Table 2 summarizes the data on hormonal control (GH and IGF-I) for those patients in the third clinical trial who
`received all 12 injections of Sandostatin LAR® Depot.
`
`Table 2
`
`Hormonal Response in Acromegalic Patients Receiving 12 Injections During’ Treatment with Sandostatin
`LAR®Depot
`
`Mean Hormone Level
`
`GH < 5.0 ng/mL
`
`< 2.5 ng/mL
`
`< 1.0 ng/mL
`
`Sandostatin®
`Injection S.C.
`N
`
`116/122
`
`84/122
`
`25/122
`
`Depot
`
`N
`
`118/122
`
`80/122
`
`28/122
`
`%
`
`97
`
`66
`
`23
`
`
`
`IGF-I normalized|82/122 67 82/122 67
`
`
`
`normalized Sandostatin LAR®
`
`
`
`GH < 5.0 ng/mL +IGF-I|80/122 66
`
`82/122
`67
`
`normalized
`
`<2.5 ng/mL +IGF-I|65/122 53
`
`70/122
`57
`
`normalized
`
`
`
`< 1.0 ng/mL + IGF-I
`
`23/122
`
`19
`
`27/122
`
`22
`
`! Average of monthly levels of GH and IGF-I over the course ofthe trial
`
`West-Ward Pharm.
`Exhibit 1060
`Page 005
`
`West-Ward Pharm.
`Exhibit 1060
`Page 005
`
`

`

`5
`
`For the 122 patients in Table 2, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mL
`was observed in 66% receiving Sandostatin LAR® Depot. Overthe course of the trial 57% of patients maintained
`mean growth hormonelevels of <2.5 ng/mL and mean normal IGF-I levels. In comparing the hormonal response
`in thesetrials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL on
`subcutaneous 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® Depotas they
`had been on Sandostatin® Injection.
`
`Ofthe 25 patients who completedthetrials and were partial responders to Sandostatin® Injection (GH >5.0
`ng/mL but reduced by te >50%relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR® Depot
`with 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 Syndrome
`
`A 6 month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been
`shown to be responsive to Sandostatin® Injection. Sixty-seven 67 patients were randomizedatbaseline 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 megt.i.d.).
`
`|
`
`In any given month after steady-state levels of octreotide were reached, approximately 35% to 40% ofthe patients
`whoreceived Sandostatin LAR® Depotrequired supplemental subcutaneous Sandostatin® Injection therapy
`usually for a few days, to control exacerbation of carcinoid symptoms. In any given month the percentage of
`patients randomized to subcutaneous Sandostatin® Injection, who require supplemental treatment with an
`
`increased dose of Sandostatin® Injection, was similar to the percentage of patients randomized to Sandostatin
`LAR® Depot. Overthe six month treatment period patients who completed thetrial on Sandostatin LAR®
`Depot, approximately 50-70% required subcutaneous Sandostatin® Injection supplemental reseue-therapy to
`control exacerbation of carcinoid symptomsalthough steady state serum Sandostatin LAR® Depotlevels had been
`reached.
`
`Table 3 presents the average numberofdaily stools and flushing episodes in malignant carcinoid patients.
`
`West-Ward Pharm.
`Exhibit 1060
`Page 006
`
`West-Ward Pharm.
`Exhibit 1060
`Page 006
`
`

`

`Table 3
`
`Average No.of Daily Stools and Flushing Episodes
`in Patients with Malignant Carcinoid Syndrome
`
`Daily Flushing
`Episodes
`(Average No.)
`
`Baseline Last Visit|Baseline LastVisit
`
`
`
`Daily Stools
`(Average No.)
`
`30 mg
`
`Sandostatin®
`Injection S.C.
`Sandostatin
`LAR® Depot
`
`10 mg
`
`20 mg
`
`Overall, mean daily stool frequency wasas well-controlled on Sandostatin LAR® Depotas 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 acetic
`acid) levels were reduced by 38-50% in the groups randomized to Sandostatin LAR® Depot.
`
`The reductions are within the range reported in the published literature for patients treated with octreotide (about
`10-50%).
`
`Seventy-eight patients with malignant carcinoid syndrome who had participated in this 6 month trial, subsequently
`participated in a 12 month extension study in which they received 12 injections of Sandostatin LAR® Depot at
`4-week intervals. For those who remained in the extensiontrial, diarrhea and flushing were as well controlled as
`during the 6 month trial. Because malignant carcinoid disease is progressive, as expected, a numberof deaths (8
`patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional
`22% of patients prematurely discontinued Sandostatin LAR® Depot due to disease progression or worsening of
`carcinoid symptoms.
`
`INDICATIONS AND USAGE
`
`Acromegaly
`
`Sandostatin LAR® Depot is indicated for long term maintenance therapy in acromegalic patients for whom
`medical 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 be
`used in patients who have had an inadequate response to surgery or in those for whom surgical resection is not an
`
`option.
`It may also be used in patients who have received radiation and have had an inadequate therapeutic
`response (See Clinical Studies and Dosage and Administration).
`
`West-Ward Pharm.
`Exhibit 1060
`Page 007
`
`West-Ward Pharm.
`Exhibit 1060
`Page 007
`
`

`

`Carcinoid Tumors
`
`Sandostatin LAR® Depotis indicated for long-term treatment of the severe diarrhea and flushing episodes
`associated with metastatic carcinoid tumorsin patients in whom initial treatment with Sandostatin® Injection has
`been shown to be effective and tolerated.
`
`Vasoactive Intestinal Peptide Tumors (VIPomas)
`
`Sandostatin LAR® Depotis indicated for long-term treatment of the profuse watery diarrhea associated with
`VIP-secreting tumors in patients in whom initial treatment with Sandostatin® Injection has been shown to be
`effective and tolerated.
`
`|
`
`In patients with acromegaly, carcinoid syndrome and VIPomas,the effect of Sandostatin® Injection and
`Sandostatin LAR® Depoton tumorsize, rate of growth and developmentof metastases, has not been determined.
`
`CONTRAINDICATIONS
`
`Sensitivity to this drug or any of its components.
`
`WARNINGS
`
`Adverse events that have been reported in patients receiving Sandostatin® Injection can also be expected in
`patients receiving Sandostatin LAR® Depot.
`Incidencefigures in the WARNINGS and ADVERSE
`REACTIONSsections, below, are those obtainedin clinical trials of Sandostatin® Injection and Sandostatin LAR
`® Depot.
`
`Gallbladder and Related Events
`
`Single doses of Sandostatin® Injection have been shown to inhibit gallbladder contractility and decrease bile
`secretion in normal volunteers.In clinical trials with Sandostatin® Injection (primarily patients with acromegaly
`or psoriasis) in patients who had not previously received octreotide, the incidenceofbiliary tract abnormalities was
`63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in
`patients who received Sandostatin® Injection for 12 months or longer was 52%. Theincidenceofgallbladder
`abnormalities did not appear to be related to age, sex or dose but wasrelated to duration of exposure.
`
`In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR® Depot for 12 months or
`longer, 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% ofmalignantcarcinoid patients who received Sandostatin LAR® Depot for up to 18 months
`|
`developed newbiliary abnormalities including gallstones, sludge and dilatation. New gallstones occurred inatotal
`of24% ofpatients.
`|
`
`Acrossalltrials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic
`hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending
`cholangitis during Sandostatin® Injection therapy and died. Despite the high incidence of new gallstones in
`patients receiving octreotide, 1% patients developed acute symptoms requiring cholecystectomy.
`
`|
`
`PRECAUTIONS(see Adverse Reactions)
`
`General
`
`GH-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
`
`West-Ward Pharm.
`Exhibit 1060
`Page 008
`
`West-Ward Pharm.
`Exhibit 1060
`Page 008
`
`

`

`hormone, which mayresult in hypothyroidism. Cardiac conduction abnormalities have also occurred during
`treatment with octreotide.
`
`8
`
`Glucose Metabolism
`
`The hypoglycemia or hyperglycemia which occurs during octreotide therapy is usually mild, but may result in overt
`diabetes mellitus or necessitate dose changesin insulin or other hypoglycemic agents. Severe hyperglycemia,
`subsequent pneumonia, and death following initiation of Sandostatin® Injection therapy was reported in one
`patient with no history of hyperglycemia (see Adverse Reactions).
`
`Thyroid Function
`
`Hypothyroidism has been reported in acromegaly and carcinoid patients receiving octreotide therapy. Baseline and
`periodic assessmentof thyroid function (TSH,total and/or free T4) is recommendedduring chronic octreotide
`therapy (see Adverse Reactions).
`
`Cardiac Function
`
`In both acromegalic and carcinoid syndromepatients, bradycardia, arrhythmias and conduction abnormalities have
`been 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.
`
`Therelationship of these events to octreotide acetate is not established because manyofthese patients have
`underlying cardiac disease (see Precautions). Dose adjustments in drugs such as beta-blockers that have
`bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of
`Sandostatin® 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).
`
`Nutrition
`
`Octreotide may alter absorption ofdietary fats in some patients.
`Depressed vitamin Bj? levels and abnormal Schilling’s tests have been observed in somepatients receiving
`octreotide therapy, and monitoring of vitamin B12 levels is recommendedduring therapy with Sandostatin LAR®
`Depot.
`
`|
`
`Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. tract in patients with
`conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may
`rise excessively when the fluid loss is reversed. Patients on
`
`TPN andoctreotide should have periodic monitoring of zinc levels.
`
`Information for Patients
`
`Patients with carcinoid tumors and VIPomasshould be advised to adhere closely to their scheduled return visits for
`reinjection 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 control
`of GH and IGF-I levels.
`
`Laboratory Tests
`
`Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend
`on the specific tumor. Based on diagnosis, measurementof the following substances may be useful in monitoring
`the progress of therapy:
`
`Acromegaly:
`
`Growth Hormone, IGF-I (somatomedin C)
`
`Responsivenessto octreotide may be evaluated by determining growth hormonelevels at 1-4 hour
`intervals for 8-12 hours after subcutaneousinjection of Sandostatin® Injection (not Sandostatin
`LAR® Depot). Alternatively, a single measurement of IGF-I (somatomedin C) level may be
`made two weeksafter initiation of Sandostatin® Injection or dosage change. After patients are
`
`West-Ward Pharm.
`Exhibit 1060
`Page 009
`
`West-Ward Pharm.
`Exhibit 1060
`Page 009
`
`

`

`9
`
`switched from Sandostatin® Injection to Sandostatin LAR® Depot, GH and IGF-I
`determinations may be madeafter 3 monthly-injections of Sandostatin LAR® Depot. (Steady
`state serum levels of octreotide are reached only after a period of 3 months of monthly injections.)
`GHcan be determined using the mean of4 assays taken at 1 hour intervals. IGF-I can be
`determined with a single assay. All GH and IGF-I determinations should be made 4 weeksafter
`the previous Sandostatin LAR® Depot.
`
`Carcinoid:
`
`5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P
`
`ViIPoma:
`
`VIP (plasma vasoactive intestinal peptide)
`
`Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see
`PRECAUTIONS — General).
`
`Drug Interactions
`
`Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of
`orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease
`blood levels of cyclosporine andresult in transplant rejection.
`
`Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control
`fluid and electrolyte balance, may require dose adjustments of these therapeutic agents.
`
`Drug Laboratory Test Interactions
`
`No known interference exists with clinical laboratory tests, including amine or peptide determinations.
`
`Carcinogenesis/Mutagenesis/Impairmentof Fertility
`
`Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin®. No mutagenic potential
`of the polymeric carrier in Sandostatin LAR® Depot, €D,L-lactic and glycolic acids copolymer}, was observed in
`the Ames mutagenicity test.
`
`|
`
`No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at
`doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous
`study in rats administered octreotide, a 27% and 12% incidence ofinjection site sarcomas or squamouscell
`carcinomas wasobserved in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the
`human 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 of
`the rat to repeated subcutaneousinjections at the samesite. Rotating injection sites would prevent chronicirritation
`in humans. There have been noreports of injection site tumors in patients treated with Sandostatin® Injection for
`at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females
`compared to 7% in the saline control females and 0% in the vehicle control females. The presence of endometritis
`coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine
`dilatation suggest that the uterine tumors were associated with estrogen dominancein the aged female rats which
`does not occur in humans.
`
`Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure
`based on body surface area.
`
`Pregnancy Category B
`
`Reproduction studies have been performedin rats and rabbits at doses up to 16 times the highest human dose based
`on 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 reproduction
`studies are not always predictive of human response, this drug should be used during pregnancyonlyif clearly
`needed.
`
`West-Ward Pharm.
`Exhibit 1060
`Page 010
`
`West-Ward Pharm.
`Exhibit 1060
`Page 010
`
`

`

`Nursing Mothers
`
`10
`
`It is not known whetherthis drug is excreted in human milk. Because many drugs are excreted in milk, caution
`should be exercised when Sandostatin LAR® Depotis administered to a nursing woman.
`
`Pediatric Use
`
`Sandostatin LAR® Depothas not been studied in pediatric patients.
`
`Experience with Sandostatin® Injection in the pediatric population is limited. Its use has been primarily in patients
`with congenital hyperinsulinism (also called nesidioblastosis). The youngest patient to receive the drug was 1
`month 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 treated
`with Sandostatin® Injection for more than 1 year; catch-up growth occurred after Sandostatin® Injection was
`discontinued. A 16 month old male with enterocutaneousfistula developed sudden abdominal pain and increased
`nasogastric drainage and died 8 hoursafter 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 chronic
`octreotide therapy (See WARNINGS). Few patients, however, develop acute symptoms requiring cholecystectomy.
`
`Cardiac
`
`In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and
`arrhythmias developed in 9% of patients during Sandostatin® Injection therapy. Electrocardiograms were
`
`performedonlyin carcinoid patients receiving Sandostatin LAR® Depot. In carcinoid syndromepatients sinus
`bradycardia developed in 19%; conduction abnormalities occurred in 9%, and arrh
`ias developed in 3%. The
`relationship of these events to octreotide acetate is not established because many of theses patients have underlying
`cardiac disease (see Precautions).
`
`Gastrointestinal
`
`The most common symptomsare gastrointestinal. The overall incidence of the most frequent of these symptoms
`in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 4.
`Table 4
`
`Number (“) of Acromegalic Patients with Common G.I. Adverse Events
`
`Sandostatin®
`Injection $.C.
`
`tid
`
`West-Ward Pharm.
`Exhibit 1060
`Page 011
`
`West-Ward Pharm.
`Exhibit 1060
`Page 011
`
`

`

`Diarrhea
`
`Abdominal Pain
`
`Vomiting
`
`or Discomfort
`
`Flatulence
`
`Constipation
`Nausea
`
`Only 2.6% of the patients on Sandostatin® Injection in U.S. clinical trials discontinued therapy due to these
`symptoms. No acromegalic patient receiving Sandostatin LAR® Depotdiscontinued therapy for a G.I. event.
`
`In patients receiving Sandostatin LAR® Depotthe incidence of diarrhea was dose-related. Diarrhea, abdominal
`pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR® Depot.
`Thereafter, new cases of these events were uncommon Thevast majority of these events were mild to moderate in
`severity.
`
`In rare instances gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive
`abdominaldistention, severe epigastric pain, abdominal tenderness, and guarding.
`
`Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4% to 6% ofpatients.
`
`In a clinical trial of carcinoid syndrome, nausea, abdominalpain, and flatulence were reported in 27% to 38% and
`constipation or vomiting in 15% to 21% ofpatients treated with Sandostatin LAR® Depot. Diarrhea was reported
`as an adverse event in enly 14% of patients but since most of the patients had diarrhea as a symptom of carcinoid
`syndrome,it is difficult to assess the actual incidence of drug-related di