CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. BYNFEZIA Pen (octreotide acetate) 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. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea).. 12.2 Pharmacodynamics. Octreotide substantially reduces growth hormone and/or IGF-I levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In clinical trials the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.1)]. Octreotide may suppress secretion of thyroid stimulating hormone (TSH) [see Warnings and Precautions (5.3)].. 12.3 Pharmacokinetics. AbsorptionAfter subcutaneous injection, octreotide is absorbed and completely from the injection site. Peak concentrations of 5.2 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. Peak concentrations and area under the curve values were dose proportional after subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg three times day (1,500 mcg/day). DistributionIn healthy volunteers the distribution of octreotide from plasma was rapid (t1/2 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in concentration-independent manner. Binding was mainly to lipoprotein and, to lesser extent, to albumin. EliminationThe elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1-3 minutes with the natural hormone. The duration of action of octreotide injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. mean peak concentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 +- 8.5 and the total body clearance was increased to 18 L/hr. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals. Specific PopulationsGeriatric PatientsIn an elderly population, dose adjustments may be necessary due to significant increase in the half-life (46%) and significant decrease in the clearance (26%) of the drug [see Use in Specific Populations (8.5)]. Patients with Renal Impairment In patients with renal impairment the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (ClCR 40-60 mL/min) octreotide t1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (ClCR 10-39 mL/min) t1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (ClCR <10 mL/min) t1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr) [see Use in Specific Populations (8.6)]. Patients with Hepatic ImpairmentPatients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. Drug Interaction Studies Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes [see Drug Interactions (7.5)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are described below and elsewhere in the labeling:Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.1)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2)] Thyroid Function Abnormalities [see Warnings and Precautions (5.3)] Cardiac Function Abnormalities [see Warnings and Precautions (5.4)] Decreased Vitamin B12 Levels and Abnormal Schillings Tests [see Warnings and Precautions (5.5)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.1)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2)] Thyroid Function Abnormalities [see Warnings and Precautions (5.3)] Cardiac Function Abnormalities [see Warnings and Precautions (5.4)] Decreased Vitamin B12 Levels and Abnormal Schillings Tests [see Warnings and Precautions (5.5)] Adverse reactions with BYNFEZIA Pen use include: (6.1) Diarrhea, loose stools, nausea and abdominal discomfort in 30% of patients with acromegaly and 5% of patients with carcinoid tumors and VIPomasGallstones and sinus bradycardia in 25% in patients with acromegalyTo report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Diarrhea, loose stools, nausea and abdominal discomfort in 30% of patients with acromegaly and 5% of patients with carcinoid tumors and VIPomas. Gallstones and sinus bradycardia in 25% in patients with acromegaly. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.The safety of BYNFEZIA Pen has been established based on clinical studies of octreotide acetate injection. Below is description of the adverse reactions from the clinical studies. Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide therapy. Single doses of octreotide have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials [primarily patients with acromegaly or psoriasis (BYNFEZIA Pen is not indicated for the treatment of psoriasis)], the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide for 12 months or longer was 52%. Less than 2% of patients treated with octreotide for month or less developed gallstones. The incidence of gallstones did not appear related to age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. 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 octreotide therapy and died. Cardiac In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients. Gastrointestinal Diarrhea, loose stools, nausea and abdominal discomfort were each seen in 34%-61% of acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5%-10% of patients with other disorders.The frequency of these symptoms was not dose-related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients.In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. Hypoglycemia and Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, and in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 6% during octreotide therapy. In patients without acromegaly, hypothyroidism has been reported in several patients. Other Adverse Reactions Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Several cases of pancreatitis have been reported. Other Adverse Reactions 1%-4% Other reactions observed in 1%-4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance and depression. Other Adverse Reactions <1% Reactions reported in less than 1% of patients are: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary: rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint effusion, muscle pain, Raynauds phenomenon; Cardiovascular: chest pain, shortness of breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease, syncope, tremor, seizure, vertigo, Bells Palsy, paranoia, pituitary apoplexy, increased intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus, gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital: nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous: otitis, allergic reaction, increased CK, weight loss. Antibodies to OctreotideEvaluation of 20 patients treated for at least months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide were subsequently reported in three patients and resulted in prolonged duration of drug action in two patients. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during the postapproval use of octreotide acetate injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Gastrointestinal: intestinal obstructionHematologic: thrombocytopenia.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility. Studies in laboratory animals have demonstrated no mutagenic potential of octreotide. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks at doses up to 2,000 mcg/kg/day (8 the human exposure based on body surface area). In 116-week subcutaneous study in rats, 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 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 subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with octreotide for up to years. There was also 15% incidence of uterine adenocarcinomas in the 1,250 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 dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents x the human exposure based on body surface area.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Acromegaly: Initiate dosage at 50 mcg three times daily. Typical dosage is 100 mcg three times day. (2.2) Carcinoid Tumors: 100-600 mcg daily in 2-4 divided doses for first weeks (2.3)VIPomas: 200-300 mcg daily in 2-4 divided doses for first weeks (2.4)See Full Prescribing Information for laboratory monitoring recommendations (2.1, 2.2, 2.3, 2.4) Administered subcutaneously; alternate injection site periodically (2.5). Acromegaly: Initiate dosage at 50 mcg three times daily. Typical dosage is 100 mcg three times day. (2.2) Carcinoid Tumors: 100-600 mcg daily in 2-4 divided doses for first weeks (2.3). VIPomas: 200-300 mcg daily in 2-4 divided doses for first weeks (2.4). See Full Prescribing Information for laboratory monitoring recommendations (2.1, 2.2, 2.3, 2.4) Administered subcutaneously; alternate injection site periodically (2.5). 2.1Laboratory Testing Prior to BYNFEZIA Pen Initiation. Assess baseline thyroid function before initiation of BYNFEZIA Pen therapy and monitor periodically [see Warnings and Precautions (5.3)]. Assess baseline thyroid function before initiation of BYNFEZIA Pen therapy and monitor periodically [see Warnings and Precautions (5.3)]. 2.2 Recommended Dosage in Acromegaly. Initiate dosing at 50 mcg subcutaneously three times day to improve tolerability to gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. Measure IGF-I levels every weeks after BYNFEZIA Pen initiation or dosage change to guide titration. Alternatively, measuring growth hormone levels at 1-4 hour intervals for 8-12 hours after BYNFEZIA Pen administration can guide titration of dose. The goal is to achieve growth hormone levels less than ng/mL or IGF-I levels within normal reference ranges for age and sex.The typical dosage is 100 mcg subcutaneously three times day, but some patients require up to 500 mcg three times day. Doses greater than 300 mcg daily seldom result in additional benefit; if an increase in dose fails to provide additional benefit, reduce the dosage. Once biochemical normalization, or maximal benefit is achieved, re-evaluate IGF-I or growth hormone levels at 6-month intervals.Withdraw BYNFEZIA Pen yearly for approximately weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I levels increase and signs and symptoms recur, BYNFEZIA Pen therapy may be resumed at the dose used at the time of BYNFEZIA Pen discontinuation.. Initiate dosing at 50 mcg subcutaneously three times day to improve tolerability to gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. Measure IGF-I levels every weeks after BYNFEZIA Pen initiation or dosage change to guide titration. Alternatively, measuring growth hormone levels at 1-4 hour intervals for 8-12 hours after BYNFEZIA Pen administration can guide titration of dose. The goal is to achieve growth hormone levels less than ng/mL or IGF-I levels within normal reference ranges for age and sex.. The typical dosage is 100 mcg subcutaneously three times day, but some patients require up to 500 mcg three times day. Doses greater than 300 mcg daily seldom result in additional benefit; if an increase in dose fails to provide additional benefit, reduce the dosage. Once biochemical normalization, or maximal benefit is achieved, re-evaluate IGF-I or growth hormone levels at 6-month intervals.. Withdraw BYNFEZIA Pen yearly for approximately weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I levels increase and signs and symptoms recur, BYNFEZIA Pen therapy may be resumed at the dose used at the time of BYNFEZIA Pen discontinuation.. 2.3Recommended Dosage for Carcinoid Tumors. The recommended daily dosage of BYNFEZIA Pen during the first weeks of therapy ranges from 100 mcg daily to 600 mcg daily in to divided doses (mean daily dosage is 300 mcg).In clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1,500 mcg daily. Experience with doses above 750 mcg daily is limited.Monitor patients urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin, and plasma Substance P.. The recommended daily dosage of BYNFEZIA Pen during the first weeks of therapy ranges from 100 mcg daily to 600 mcg daily in to divided doses (mean daily dosage is 300 mcg).. In clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1,500 mcg daily. Experience with doses above 750 mcg daily is limited.. Monitor patients urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin, and plasma Substance P.. 2.4Recommended Dosage for VIPomas. The recommended daily dosage of BYNFEZIA Pen during the first weeks of therapy ranges from 200 mcg daily to 300 mcg daily in to divided doses. Adjust the dosage to achieve therapeutic response; daily dosage is 150 mcg to 750 mcg but usually doses above 450 mcg daily are not required.Monitor patients plasma vasoactive intestinal peptide (VIP).. The recommended daily dosage of BYNFEZIA Pen during the first weeks of therapy ranges from 200 mcg daily to 300 mcg daily in to divided doses. Adjust the dosage to achieve therapeutic response; daily dosage is 150 mcg to 750 mcg but usually doses above 450 mcg daily are not required.. Monitor patients plasma vasoactive intestinal peptide (VIP).. 2.5Important Administration Instructions. Inspect visually for particulate matter and discoloration. Only use BYNFEZIA Pen if the solution appears colorless with no visible particles.BYNFEZIA Pen should be at room temperature before injecting to reduce potential injection site reactions.Administer BYNFEZIA Pen by subcutaneous injection into the abdomen, the front of the middle thighs, or the back/outer area of the upper arms.Rotate injection sites so that the same site is not used repeatedly. Injection sites should be at least inches away from your last injection site.Provide proper training to patients and/or caregivers on the administration of BYNFEZIA Pen prior to use according to the Instructions for Use.. Inspect visually for particulate matter and discoloration. Only use BYNFEZIA Pen if the solution appears colorless with no visible particles.. BYNFEZIA Pen should be at room temperature before injecting to reduce potential injection site reactions.. Administer BYNFEZIA Pen by subcutaneous injection into the abdomen, the front of the middle thighs, or the back/outer area of the upper arms.. Rotate injection sites so that the same site is not used repeatedly. Injection sites should be at least inches away from your last injection site.. Provide proper training to patients and/or caregivers on the administration of BYNFEZIA Pen prior to use according to the Instructions for Use.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Cyclosporine: May decrease cyclosporine concentrations with concomitant use of BYNFEZIA Pen (7.1)Bromocriptine: May increase bromocriptine concentrations with concomitant use of BYNFEZIA Pen (7.3)Other Concomitant Drugs: Dosage adjustment of calcium channel blockers and drugs that control fluid and electrolyte balance may be required (7.4). 7.1 Cyclosporine. Concomitant administration of BYNFEZIA Pen with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.. 7.2 Insulin and Oral Hypoglycemic Drugs. Octreotide inhibits the secretion of insulin and glucagon. Monitor blood glucose levels upon BYNFEZIA Pen initiation or dose adjustment. Patients with diabetes mellitus may require dose adjustments of insulin or other antidiabetic agents [see Warnings and Precautions (5.2)]. 7.3 Bromocriptine. Concomitant administration of BYNFEZIA Pen and bromocriptine increases the availability of bromocriptine.. 7.4 Other Concomitant Drug Therapy. Patients receiving beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may require dose adjustments of these therapeutic agents.Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.. 7.5 Drug Metabolism Interactions. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormones. Since octreotide may have this effect, concomitant use of BYNFEZIA Pen with other drugs mainly metabolized by CYP3A4 and which have low therapeutic index (e.g., quinidine) should be used with caution and increased monitoring may be required.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BYNFEZIA Pen is somatostatin analogue indicated for:Reduction of growth hormone (GH) and insulin-like growth factor (IGF-1) [somatomedin C] in adult patients with acromegaly who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses (1.1) Treatment of severe diarrhea/flushing episodes associated with metastatic carcinoid tumors in adult patients (1.2) Treatment of profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas) in adult patients (1.3) Limitations of Use:In patients with acromegaly, the effect of BYNFEZIA Pen on improvement in clinical signs and symptoms, reduction in tumor size and rate of growth, has not been determined. (1.4) In patients with carcinoid syndrome and VIPomas, the effect of BYNFEZIA Pen on size, rate of growth and development of metastases, has not been determined. (1.4) Reduction of growth hormone (GH) and insulin-like growth factor (IGF-1) [somatomedin C] in adult patients with acromegaly who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses (1.1) Treatment of severe diarrhea/flushing episodes associated with metastatic carcinoid tumors in adult patients (1.2) Treatment of profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas) in adult patients (1.3) In patients with acromegaly, the effect of BYNFEZIA Pen on improvement in clinical signs and symptoms, reduction in tumor size and rate of growth, has not been determined. (1.4) In patients with carcinoid syndrome and VIPomas, the effect of BYNFEZIA Pen on size, rate of growth and development of metastases, has not been determined. (1.4) 1.1 Acromegaly. BYNFEZIA Pen is indicated to reduce blood levels of growth hormone (GH) and insulin-like growth factor (IGF-1) [somatomedin C] in adult patients with acromegaly who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.. 1.2 Carcinoid Tumors. BYNFEZIA Pen is indicated for the treatment of adult patients with severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.. 1.3 Vasoactive Intestinal Peptide Tumors (VIPomas). BYNFEZIA Pen is indicated for the treatment of adult patients with the profuse watery diarrhea associated with VIP-secreting tumors. 1.4 Limitations of Use. In patients with acromegaly, the effect of BYNFEZIA Pen on improvement in clinical signs and symptoms, reduction in tumor size, and rate of growth has not been determined. In patients with carcinoid syndrome and VIPomas, the effect of BYNFEZIA Pen on the tumor size, rate of growth and development of metastases has not been determined.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Cholelithiasis and Complications of CholelithiasisAdvise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of cholelithiasis (e.g., cholecystitis, cholangitis and pancreatitis) [see Warnings and Precautions (5.1)]. Hypoglycemia and HyperglycemiaAdvise patients to contact their healthcare provider if they have problems with blood sugar levels, either too high (hyperglycemia) or too low (hypoglycaemia) [see Warnings and Precautions (5.2)]. Thyroid Function AbnormalitiesInform patients that their thyroid function will be assessed at baseline and periodically during treatment [see Warnings and Precautions (5.3)]. Cardiac Function AbnormalitiesInform patients to contact the health care provider in case they notice irregular heart beat [see Warnings and Precautions (5.4)]. Decreased Vitamin B12 Levels and Abnormal Schillings TestsInform patients that Vitamin B12 levels may be monitored during the treatment [see Warnings and Precautions (5.5)]. Pregnancy Inform female patients that treatment with BYNFEZIA Pen may result in unintended pregnancy [see Use in Specific Populations (8.3)]. Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512 Manufactured by:Sun Pharmaceutical Industries Ltd.Halol-Baroda Highway,Halol-389 350, Gujarat, India Revised: 04/2020.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility. Studies in laboratory animals have demonstrated no mutagenic potential of octreotide. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks at doses up to 2,000 mcg/kg/day (8 the human exposure based on body surface area). In 116-week subcutaneous study in rats, 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 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 subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with octreotide for up to years. There was also 15% incidence of uterine adenocarcinomas in the 1,250 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 dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents x the human exposure based on body surface area.. 13.2Animal Toxicology and/or Pharmacology. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and revealed no evidence of harm to the fetus due to octreotide.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter subcutaneous injection, octreotide is absorbed and completely from the injection site. Peak concentrations of 5.2 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. Peak concentrations and area under the curve values were dose proportional after subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg three times day (1,500 mcg/day). DistributionIn healthy volunteers the distribution of octreotide from plasma was rapid (t1/2 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in concentration-independent manner. Binding was mainly to lipoprotein and, to lesser extent, to albumin. EliminationThe elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1-3 minutes with the natural hormone. The duration of action of octreotide injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. mean peak concentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 +- 8.5 and the total body clearance was increased to 18 L/hr. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals. Specific PopulationsGeriatric PatientsIn an elderly population, dose adjustments may be necessary due to significant increase in the half-life (46%) and significant decrease in the clearance (26%) of the drug [see Use in Specific Populations (8.5)]. Patients with Renal Impairment In patients with renal impairment the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (ClCR 40-60 mL/min) octreotide t1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (ClCR 10-39 mL/min) t1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (ClCR <10 mL/min) t1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr) [see Use in Specific Populations (8.6)]. Patients with Hepatic ImpairmentPatients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. Drug Interaction Studies Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes [see Drug Interactions (7.5)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from case reports with octreotide acetate use in pregnant women are insufficient to identify drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with intravenous administration of octreotide to pregnant rats and rabbits during organogenesis at doses and 13-times, respectively, the maximum recommended human dose (MRHD) of 1,500 mcg/day based on body surface area. Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from pre- and post-natal study of octreotide at intravenous doses below the MRHD based on body surface area (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal DataIn embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of octreotide up to mg/kg/day during the period of organogenesis. slight reduction in body weight gain was noted in pregnant rats at 0.1 and mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At mg/kg/day in rats and rabbits, the dose multiple was approximately and 13 times, respectively, at the highest recommended human dose of 1,500 mcg/day based on body surface area. In pre- and post-natal development rat study at intravenous doses of 0.02-1 mg/kg/day, transient growth retardation of the offspring was observed at all doses which was possibly consequence of growth hormone inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1,500 mcg/day, based on body surface area.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3) 8.1 Pregnancy. Risk SummaryAvailable data from case reports with octreotide acetate use in pregnant women are insufficient to identify drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with intravenous administration of octreotide to pregnant rats and rabbits during organogenesis at doses and 13-times, respectively, the maximum recommended human dose (MRHD) of 1,500 mcg/day based on body surface area. Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from pre- and post-natal study of octreotide at intravenous doses below the MRHD based on body surface area (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal DataIn embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of octreotide up to mg/kg/day during the period of organogenesis. slight reduction in body weight gain was noted in pregnant rats at 0.1 and mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At mg/kg/day in rats and rabbits, the dose multiple was approximately and 13 times, respectively, at the highest recommended human dose of 1,500 mcg/day based on body surface area. In pre- and post-natal development rat study at intravenous doses of 0.02-1 mg/kg/day, transient growth retardation of the offspring was observed at all doses which was possibly consequence of growth hormone inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1,500 mcg/day, based on body surface area.. 8.2Lactation. Risk SummaryThere is no information available on the presence of octreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats (see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BYNFEZIA Pen, and any potential adverse effects on the breastfed child from BYNFEZIA Pen or from the underlying maternal condition. Data Following subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at low concentration compared to plasma (milk/plasma ratio of 0.009).. 8.3Females and Males of Reproductive Potential. Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of reduction in GH levels and normalization of IGF-1 concentration in acromegalic females treated with octreotide may lead to improved fertility.. 8.4 Pediatric Use. Safety and efficacy of BYNFEZIA Pen in pediatric patients have not been established. In post-marketing reports, serious adverse reactions, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide injection use in pediatric patients, most notably in children under years of age.. 8.5 Geriatric Use. Clinical studies of octreotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.. 8.6 Renal Impairment. In patients on dialysis, the half-life of octreotide may increase, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected (5.1) Hypoglycemia or Hyperglycemia: Monitor glucose and adjust antidiabetic treatment as needed. (5.2) Thyroid Function Abnormalities: Hypothyroidism may occur. Assess baseline thyroid function before initiation and monitor periodically (5.3) Cardiac Function: Bradycardia, arrhythmia, or conduction abnormalities may occur. Drugs that have bradycardia effects may need dosage adjustments (5.4). Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected (5.1) Hypoglycemia or Hyperglycemia: Monitor glucose and adjust antidiabetic treatment as needed. (5.2) Thyroid Function Abnormalities: Hypothyroidism may occur. Assess baseline thyroid function before initiation and monitor periodically (5.3) Cardiac Function: Bradycardia, arrhythmia, or conduction abnormalities may occur. Drugs that have bradycardia effects may need dosage adjustments (5.4). 5.1Cholelithiasis and Complications of Cholelithiasis. BYNFEZIA Pen may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, pancreatitis and requiring cholecystectomy in patients taking octreotide [see Adverse Reactions (6)]. Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue BYNFEZIA Pen and treat appropriately. 5.2Hyperglycemia and Hypoglycemia. BYNFEZIA Pen alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia, hyperglycemia, or overt diabetes mellitus. In patients with acromegaly, 3% developed hypoglycemia and 16% developed hyperglycemia during treatment with octreotide. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide was reported in one patient with no history of hyperglycemia [see Adverse Reactions (6)]. In patients with type diabetes mellitus, BYNFEZIA Pen is likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, sometimes severe, has been reported in these patients. In patients without diabetes and patients with type diabetes with partially intact insulin reserves, BYNFEZIA Pen may result in decreases in plasma insulin levels and hyperglycemia. Monitor glycemic control for all patients and adjust antidiabetic treatment as necessary.. 5.3Thyroid Function Abnormalities. BYNFEZIA Pen suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. In patients with acromegaly, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving octreotide. Assess thyroid function at baseline and periodically during treatment with BYNFEZIA Pen [see Adverse Reactions (6)].. 5.4Cardiac Function Abnormalities. Cardiac conduction abnormalities have occurred during treatment with octreotide. In patients with acromegaly, bradycardia (<50 bpm) developed in 25%, conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during treatment with octreotide. Other ECG changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early wave progression. These ECG changes may occur in patients with acromegaly. In one patient with acromegaly and severe congestive heart failure (CHF), initiation of octreotide resulted in worsening of CHF with improvement when drug was discontinued and worsened when octreotide was restarted [see Adverse Reactions (6)]. Dosage adjustments of concomitantly used drugs that have bradycardia effects (i.e. beta-blockers) may be necessary [see Drug Interactions (7.4)]. 5.5Decreased Vitamin B12 Levels and Abnormal Schillings Tests. BYNFEZIA Pen may alter absorption of dietary fats in some patients. Decreased vitamin B12 levels and abnormal Schillings tests have been observed in some patients receiving octreotide. Monitor vitamin B12 levels during treatment with BYNFEZIA Pen.