BYNFEZIA Pen (Page 2 of 5)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 a description of the adverse reactions from the clinical studies.

Gallbladde r 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 1 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. 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 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.

H y poglycemia and H y pergl y cemia

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.

Othe r Adverse Reactions

Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Several cases of pancreatitis have been reported.

Othe r 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.

Othe r 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, Raynaud’s 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, Bell’s 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 Octreotide

Evaluation of 20 patients treated for at least 6 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal: intestinal obstruction

Hematologic: thrombocytopenia

7 DRUG INTERACTIONS

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 a low therapeutic index (e.g., quinidine) should be used with caution and increased monitoring may be required.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

R isk Summary

Available data from case reports with octreotide acetate use in pregnant women are insufficient to identify a 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 7 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 a 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.

D ata

A nimal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7 and 13 times, respectively, at the highest recommended human dose of 1,500 mcg/day based on body surface area.

In a pre- and post-natal development rat study at intravenous doses of 0.02–1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a 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.