Summary Of Exposure |
A) USES: Octreotide is a somatostatin analogue, used to treat patients who have not responded to and tolerated octreotide subQ injection for acromegaly, severe diarrhea/flushing episodes associated with metastatic carcinoid tumors, and profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPoma-associated diarrhea). Octreotide has been used in sulfonylurea-induced hypoglycemia. It is used to inhibit insulin secretion in patients who are refractory to standard therapy with dextrose boluses and infusions. Octreotide should only be used after euglycemia has been achieved with IV dextrose as it will only prevent further episodes of hypoglycemia. Lanreotide is a somatostatin analogue with similar properties to octreotide, used in the treatment of acromegaly. It is also used to treat patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. Pasireotide is used to treat adult patients with Cushing disease for whom pituitary surgery is not an option or has not been curative.
B) PHARMACOLOGY: Octreotide acetate, a cyclic octapeptide agent, inhibits growth hormone, glucagon, and insulin more effectively than the natural hormone, somatostatin. Its suppression of luteinizing hormone's (LH) response to gonadotrophin releasing hormone (GnRH) and inhibition of the release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, and pancreatic polypeptide are similar to somatostatin's actions. The drug also reduces growth hormone and/or IGF-I (somatomedin C) in acromegaly, inhibits gallbladder contractions, reduces bile secretion and suppresses the secretion of thyroid stimulating hormone (TSH). Lanreotide acetate, an octapeptide analog of natural somatostatin, behaves similarly to that of natural somatostatin and inhibits secretion of various endocrine, neuroendocrine, exocrine and paracrine functions; thereby, normalizing growth hormones (GH) and/or insulin-like growth factor-1 (IGF-1) levels in acromegalic patients. Pasireotide diaspartate is a cyclohexapeptide somatostatin analogue that exerts its activity by binding to somatostatin receptors. Adrenocorticotropic hormone (ACTH) secretion is inhibited leading to decreased cortisol secretion.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) OCTREOTIDE: MOST COMMON: Anorexia, nausea, vomiting, diarrhea and steatorrhea, constipation, abdominal discomfort, and flatulence. OTHER EFFECTS: Gallstones, hypoglycemia and hyperglycemia, dizziness, pancreatitis, hypothyroidism, sinus bradycardia, conduction abnormalities, dysrhythmias, thrombocytopenia, anemia, and hepatitis.
2) LANREOTIDE: MOST COMMON: Diarrhea, cholelithiasis, abdominal pain, nausea, vomiting, injection site reactions, musculoskeletal pain, headache, hyperglycemia, hypertension. OTHER EFFECTS: Bradycardia, pancreatitis, constipation, hypersensitivity reaction, dizziness, depression, and dyspnea.
3) PASIREOTIDE: MOST COMMON: Diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. OTHER EFFECTS: Bradycardia, prolonged QT interval, hypertension, peripheral edema, injection site reactions, hypoglycemia, vomiting, pancreatitis, elevated liver enzymes, asthenia, and nasopharyngitis.
E) WITH POISONING/EXPOSURE
1) Overdose data is limited. OCTREOTIDE: Hypoglycemia, flushing, dizziness and nausea have been reported following an overdose of octreotide. LANREOTIDE: In postmarketing experience, cases of overdose have not resulted in an adverse reaction. PASIREOTIDE: Diarrhea occurred frequently after healthy volunteers received pasireotide up to 2.1 mg twice daily.
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) BRADYCARDIA 1) WITH THERAPEUTIC USE a) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, decreased heart rate of less than 60 beats/min developed in 23% (19/81) of lanreotide-treated patients as compared with 16% (15/94) of placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
b) OCTREOTIDE: INCIDENCE: Bradycardia of less than 50 bpm has occurred in 25% of acromegalic patients treated with octreotide. In carcinoid syndrome, bradycardia occurred in 19% of patients (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014; Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012).
c) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, sinus bradycardia was reported in 10% and 3% of patients treated with pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
B) ELECTROCARDIOGRAM ABNORMAL 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Conduction abnormalities and arrhythmias with therapeutic dosing have been reported in 3% to 10%, and 9% of acromegalic and carcinoid syndrome patients, respectively. Other ECG changes reported included: QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, non-specific ST-T wave changes, and early R wave progression (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014). No relationship was established because many patients had existing cardiac morbidity.
b) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, QT interval prolongation was reported in 6% each of patients treated with pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily. Prolongation of the QT interval has been reported following pasireotide therapy at therapeutic and above therapeutic doses (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
C) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, hypertension developed in 14% of 101 lanreotide-treated patients as compared with 5% of 103 placebo-treated patients. Severe hypertension developed in 1% of lanreotide-treated patients as compared with 0% of placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
b) OCTREOTIDE: In clinical trials, 12.6% of 261 patients with acromegaly developed hypertension after receiving IM octreotide (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014)
c) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, hypertension was reported in 10% each of patients treated with pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
D) MYOCARDIAL INFARCTION 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Myocardial infarction was reported with octreotide acetate use (IV or subQ preparation), mainly in patients with cardiovascular risk factors (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
E) PERIPHERAL EDEMA 1) WITH THERAPEUTIC USE a) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, peripheral edema was reported in 11% and 10% of patients treated with pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DISORDER OF RESPIRATORY SYSTEM 1) WITH THERAPEUTIC USE a) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, dyspnea developed in 6% of 101 lanreotide-treated patients as compared with 1% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
b) OCTREOTIDE: Upper respiratory tract infection, dyspnea, and flu-like symptoms have been reported in 16% to 20% of acromegalic and/or carcinoid syndrome patients receiving octreotide (Prod Info Sandostatin(R), octreotide acetate, 1999). However, a causal relationship has not been established.
B) NASOPHARYNGITIS 1) WITH THERAPEUTIC USE a) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, nasopharyngitis was reported in 12% and 14% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) DIZZINESS 1) WITH THERAPEUTIC USE a) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, dizziness developed in 9% of 101 lanreotide-treated patients as compared with 2% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
b) OCTREOTIDE: Dizziness, headache, and fatigue have been reported in 16% to 20% of acromegalic and/or carcinoid syndrome patients receiving octreotide (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014). However, a causal relationship has not been established.
2) WITH POISONING/EXPOSURE a) OCTREOTIDE: Dizziness was reported with subcutaneous doses of 2.5 milligrams (2500 micrograms) of octreotide (Prod Info Sandostatin(R), octreotide acetate, 1999).
B) HEADACHE 1) WITH THERAPEUTIC USE a) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, headache was reported in 7% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
b) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, headache developed in 16% of 101 lanreotide-treated patients as compared with 11% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
c) OCTREOTIDE: Headache has been reported with therapeutic use of these agents (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
d) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, headache was reported in 28% and 29% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Headache was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
C) ASTHENIA 1) WITH THERAPEUTIC USE a) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, asthenia was reported in 16% and 6% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
D) FATIGUE 1) WITH THERAPEUTIC USE a) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, fatigue was reported in 15% and 24% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Fatigue was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea, abdominal pain and nausea, constipation, and loose stools are common gastrointestinal events with these agents (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
b) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, diarrhea was reported in 37% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
c) OCTREOTIDE: Diarrhea, loose stools, nausea, and abdominal discomfort are common side effects seen in 30% to 58% of acromegalic patients treated with octreotide; however, these side effects are generally only seen in 5% to 10% of patients treated with octreotide for other conditions (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
d) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, diarrhea was reported in 59% and 58% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Diarrhea was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
B) FATTY STOOL 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Octreotide has been reported to interfere with the intestinal absorption of fat and may lead to steatorrhea (Plewe et al, 1986).
b) OCTREOTIDE: In one study, 5 patients with acromegaly received daily doses of 100 to 300 micrograms of octreotide for 8 to 24 weeks. Only one patient developed clinical steatorrhea (Lamberts & Del Pozo, 1986).
c) The effects of chronic octreotide on fat absorption were evaluated in eight patients with acromegaly. Fecal fat excretion was significantly increased from 7 +/- 2 grams per 24 hours before treatment to 12 +/- 2 grams per 24 hours after 17 weeks of octreotide 450 to 1500 micrograms daily (an increase of 71%); fecal fat returned to baseline after a 5-week washout period (Ho et al, 1993).
C) HYPERGASTRINEMIA 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Severe symptoms of rebound hypergastrinemia were reported in a 52-year-old man with Zollinger-Ellison syndrome following the discontinuation of octreotide therapy (Buck et al, 1987).
D) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea and vomiting are common with these agents (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
b) Nausea and vomiting have been reported in 9.6% and 10%, respectively, of patients receiving octreotide (Prod Info Sandostatin(R), octreotide acetate, 1999).
c) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, nausea was reported in 11% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
d) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, vomiting developed in 19% of 101 lanreotide-treated patients as compared with 9% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
e) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, nausea was reported in 46% and 58% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Nausea was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
2) WITH POISONING/EXPOSURE a) Nausea was reported with subcutaneous doses of 2.5 mg (2500 mcg) of octreotide (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
E) BILIARY CALCULUS 1) WITH THERAPEUTIC USE a) Cholelithiasis and severe abdominal pain have been reported in association with the use of these agents (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014; Rhodes et al, 1992; McKnight et al, 1989). In clinical trials, the incidence of gallstones or sludge in patients treated with octreotide for 12 months or longer was 52% (Prod Info Sandostatin(R), octreotide acetate, 1999).
b) Biliary colic has been reported after abrupt withdrawal of octreotide. One patient on long term octreotide developed severe but short-lived biliary colic after discontinuation of octreotide. The episodes related to a rebound hypercontractility of the gallbladder occurring after the abrupt cessation of octreotide (Sadoul et al, 1991) Sadoul et al, 1992).
c) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, new cholelithiasis was reported in 12% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
d) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, cholelithiasis developed in 14% of 101 lanreotide-treated patients as compared with 7% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014). Disappearance of gallstones has been observed within 3 months of withdrawal of therapy (Marek et al, 1994), but spontaneous resolution has also been observed during continued lanreotide therapy (Morange et al, 1994).
e) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, cholelithiasis was reported in 30% and 30% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Cholelithiasis was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
F) PANCREATITIS 1) WITH THERAPEUTIC USE a) LANREOTIDE: Pancreatitis has been reported during postmarketing use (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
b) LANREOTIDE: CASE REPORT: Acute pancreatitis was reported in a 45-year-old man who received 1 dose of lanreotide 90 mg for acromegaly. The patient presented with severe epigastric pain and a serum amylase of 1340 units/L, although other laboratory tests and abdominal ultrasound were normal. Lanreotide was stopped. After 4 days, imaging showed a distended pancreatic duct, gallbladder and bile ducts; no stones were detected. Acute pancreatitis due to functional obstructive spasm of the Sphincter of Oddi was suspected. The patient was treated with transdermal glyceryl trinitrate with resolution of symptoms and ultrasound findings within 2 weeks (Sequeira Lopes da Silva et al, 2013).
c) OCTREOTIDE: Several case reports have associated acute pancreatitis with the use of octreotide. In 2 cases, ultrasound of the gallbladder was normal (Fredenrich et al, 1991; Gradon et al, 1991) and in one case, acute pancreatitis was a complication of cholelithiasis 2 months after octreotide had been discontinued (Sadoul et al, 1991). Bodemar & Hjortswang (1996) suggested that octreotide-induced pancreatitis may result from the spasm of the sphincter of Oddi, causing retention of activated pancreatic enzymes due to outflow obstruction (Bodemar & Hjortswang, 1996).
G) DRUG-INDUCED ILEUS 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Small bowel obstruction has been reported in one patient with a jejunostomy who was receiving octreotide 50 micrograms subcutaneously every 12 hours. Bowel obstruction resolved within three days of conservative treatment (Ladefoged et al, 1989).
H) CONSTIPATION 1) WITH THERAPEUTIC USE a) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, constipation was reported in 8% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
I) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, abdominal pain was reported in 19% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
b) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, abdominal pain developed in 34% of 101 lanreotide-treated patients as compared with 24% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
c) OCTREOTIDE: Abdominal pain, increased nasogastric drainage, and death were reported in a 16-month-old boy with enterocutaneous fistula after receiving a single 100 mcg subcutaneous dose of octreotide (Prod Info Sandostatin(R), octreotide acetate, 1999).
d) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, abdominal pain was reported in 23% and 25% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Abdominal pain was among the most common adverse events reported following pasireotide diaspartate therapy (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) TOXIC HEPATITIS 1) WITH THERAPEUTIC USE a) OCTREOTIDE: CASE REPORT: Hepatitis was observed in a 50-year-old male with acromegaly after receiving octreotide 100 micrograms subcutaneously every 8 hours for approximately 6 months. Withdrawal of the drug resulted in normalization of liver enzymes within 25 days. Hepatitis recurred following rechallenge several months later, and again resolved following withdrawal of the drug (Arosio et al, 1988). Hepatitis was also reported in a patient with acromegaly after receiving octreotide which was confirmed upon rechallenge (Gonzalez-Martin et al, 1996).
B) INCREASED LIVER ENZYMES 1) WITH THERAPEUTIC USE a) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, increased ALT levels were reported in 13% and 8% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. During the phase 3 study, mean elevations in aminotransferase levels were transient, had returned to baseline values by month 4 of therapy, and were not associated with clinical symptoms of hepatic disease (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Thrombocytopenia has been reported in patients who received octreotide acetate IV/subQ preparation(Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012)
b) OCTREOTIDE: CASE REPORT: The platelet count fell from 204,000 to 56,000/mm(3) ten days after octreotide was initiated in a 39-year-old man with enterocutaneous fistula. After discontinuation of octreotide, the platelet count gradually returned to normal. No other medications known to cause thrombocytopenia were in use during this time period, thus octreotide was strongly suspected as being the causative agent (Hanna & Maull, 1990).
B) ANEMIA 1) WITH THERAPEUTIC USE a) OCTREOTIDE: In clinical trials, 15.3% of 261 patients with acromegaly developed anemia after receiving IM octreotide (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014)
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Rash and pruritus have occurred rarely in patients receiving octreotide (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
B) ALOPECIA 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Hair loss or thinning of scalp hair was reported in 4 of 9 patients treated with octreotide for acromegaly. Scalp hair returned in 3 patients after discontinuation of octreotide (Jonsson & Manhem, 1991).
C) INJECTION SITE REACTION 1) WITH THERAPEUTIC USE a) LANREOTIDE: In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, injection site reactions developed in 15% of 101 lanreotide-treated patients as compared with 7% of 103 placebo-treated patients. The symptoms included infusion site extravasation, discomfort, granuloma, hematoma, hemorrhage, induration, mass, nodule, pain, pruritus, rash, and swelling (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
b) PASIREOTIDE: During a 6-month, randomized, phase 3 study of patients with Cushing disease, injection site reaction was reported in 17% and 18% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. Symptoms included local pain, erythema, hematoma, hemorrhage, and pruritus. The reactions resolved spontaneously without need for intervention (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
D) FLUSHING 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Hot flashes severe enough to stop therapy have been reported with octreotide use (Buchler et al, 1992).
2) WITH POISONING/EXPOSURE a) OCTREOTIDE: Flushing was reported with subcutaneous doses of 2.5 mg (2500 mcg) of octreotide (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) MUSCLE PAIN 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Back pain, myalgia, arthralgia, muscle cramps, and shoulder and leg pain have been reported in a small number of patients (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
B) JOINT PAIN 1) WITH THERAPEUTIC USE a) LANREOTIDE: In pooled data from seven studies of 416 acromegalic patients treated with lanreotide, arthralgia was reported in 7% of patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) ABNORMAL GLUCOSE LEVEL 1) WITH THERAPEUTIC USE a) These agents can alter the balance between the counter-regulatory hormones (eg, insulin, glucagon and growth hormone), which may result in hypoglycemia or hyperglycemia (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014). Octreotide has been demonstrated to inhibit insulin secretion and may result in a transient deterioration in glucose tolerance upon initiation of therapy (Plewe et al, 1984). Improvement in glucose tolerance usually occurs with continued therapy in diabetic acromegalic patients (Lamberts & Del Pozo, 1986). b) In acromegaly patients treated with either subcutaneous or intragluteal octreotide, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients. In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with intragluteal injection (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998). c) LANREOTIDE 1) Hypoglycemia has also been reported (Prod Info SOMATULINE(R) DEPOT subcutaneous injection, 2013)
2) In clinical trials of patients with gastroenteropancreatic neuroendocrine tumors, hyperglycemia developed in 14% of 101 lanreotide-treated patients as compared with 5% of 103 placebo-treated patients (Prod Info SOMATULINE(R) DEPOT subcutaneous injection solution, 2014).
d) PASIREOTIDE 1) HYPOGLYCEMIA: During a 6-month, randomized, phase 3 study of patients with Cushing disease, hypoglycemia was reported in 15% and 4% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
2) DIABETES MELLITUS: During a 6-month, randomized, phase 3 study of patients with Cushing disease, diabetes mellitus was reported in 16% and 20% of patients administered pasireotide diaspartate 0.6 mg (n=82) and 0.9 mg (n=80) twice daily, respectively. During the study, most patients, including those with normal glucose status at baseline, developed worsening glycemia in the first 2 weeks of therapy. Increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were generally observed soon after treatment initiation and sustained throughout therapy. Between baseline and month 6, mean FPG levels increased from 98.6 mg/dL to 125.1 mg/dL in the pasireotide 0.6 mg group, and from 97 mg/dL to 128 mg/dL in the pasireotide 0.9 mg group. During the same time period, HbA1c increased from 5.8% to 7.2% in the pasireotide 0.6 mg group and from 5.8% to 7.3% in the pasireotide 0.9 mg group. Upon discontinuation of pasireotide, mean FPG and HbA1c levels were decreased, but remained above baseline at the 1-month follow-up visit (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
2) WITH POISONING/EXPOSURE a) OCTREOTIDE: Hypoglycemia was reported with subcutaneous doses of 2.5 mg (2500 mcg) of octreotide (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
B) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Galactorrhea has been reported in association with the use of octreotide (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
C) HYPOTHYROIDISM 1) WITH THERAPEUTIC USE a) OCTREOTIDE: Octreotide suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism (Prod Info Sandostatin(R) subcutaneous injection, intravenous injection, 2012; Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014). Biochemical hypothyroidism has been reported in 12% of patients with acromegaly treated with octreotide; 6% developed goiter and 4% required thyroid replacement therapy. In patients without acromegaly, only rare cases of hypothyroidism have occurred (Prod Info Sandostatin(R) LAR Depot intramuscular injection suspension, 2014).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) HYPERSENSITIVITY REACTION 1) WITH THERAPEUTIC USE a) LANREOTIDE: Allergic reactions, including angioedema and anaphylaxis, have been reported in postmarketing surveillance (Prod Info SOMATULINE® DEPOT(R) subcutaneous injection solution, 2014).
B) ANAPHYLAXIS 1) WITH THERAPEUTIC USE a) LANREOTIDE: Anaphylaxis, angioedema, and other allergic reactions have been reported in postmarketing surveillance (Prod Info SOMATULINE® DEPOT(R) subcutaneous injection solution, 2014).
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Reproductive |
3.20.1) SUMMARY
A) Octreotide is classified as FDA pregnancy category B and lanreotide, pasireotide, and pasireotide diaspartate are classified as FDA pregnancy category C. No teratogenic effects or reproductive toxicity were observed in rats and rabbits administered octreotide. Lanreotide has been shown to have an embryocidal effect in rats and rabbits. Pasireotide also causes fetal harm in rats and rabbits.
3.20.2) TERATOGENICITY
A) TERATOGENICITY 1) PASIREOTIDE: Maternal toxicity was observed in rats and rabbits administered subQ doses of 1 mg/kg/day (12-fold and 5-fold higher than the maximum therapeutic dose, based on AUC, respectively) and higher throughout organogenesis (Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
2) OCTREOTIDE: No teratogenic effects or reproductive toxicity were observed in rats and rabbits with octreotide doses 16 times the highest human dose based on body surface area (Prod Info SANDOSTATIN(R) solution for injection, 2008).
B) ANIMAL STUDIES 1) SKELETAL MALFORMATIONS a) PASIREOTIDE: Skeletal malformations were observed in rabbits administered a dose of 0.05 mg/kg/day (less than the maximum therapeutic exposure, based on AUC)(Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
b) PASIREOTIDE DIASPARTATE: Treatment-related increased incidences of skeletal malformations occurred at 0.05 mg/kg/day (exposures less than the maximum therapeutic exposure based on AUC comparisons across species) (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified octreotide as FDA pregnancy category B (Prod Info SANDOSTATIN(R) solution for injection, 2008).
2) The manufacturers have classified lanreotide, pasireotide, and pasireotide diaspartate as FDA pregnancy category C (Prod Info SOMATULINE(R)DEPOT subcutaneous injection, 2007; Prod Info SIGNIFOR(R) subcutaneous injection, 2012; Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
B) LACK OF EFFECT 1) OCTREOTIDE: In postmarketing evaluations, no congenital malformations were reported among pregnant women receiving octreotide for the treatment of acromegaly. Most women received doses ranging from 100 to 300 mcg/day (subQ) or 20 to 30 mg/month (IM). While most of the women were exposed during the first trimester of pregnancy, some women chose to continue treatment throughout pregnancy (Prod Info SANDOSTATIN(R) solution for injection, 2008).
C) ANIMAL STUDIES 1) EMBRYOTOXICITY a) Lanreotide has been shown to have an embryocidal effect in rats and rabbits; however, no well controlled studies have been conducted in pregnant women (Prod Info SOMATULINE(R)DEPOT subcutaneous injection, 2007).
b) PASIREOTIDE: Significantly increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites were observed in rats administered doses less than the human exposure (based on body surface area) before mating and continuing into gestation (Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
c) PASIREOTIDE DIASPARTATE: Animal studies in rats and rabbits showed pasireotide causes fetal harm when administered during pregnancy at therapeutic exposures (doses of 0.05 mg/kg/day for rats and 2 mg/kg/day for rabbits) (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
d) PASIREOTIDE DIASPARTATE: In animal studies, adverse fertility and reproductive effects, including statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites, were observed in rats dosed with pasireotide diaspartate before mating and continuing into gestation at exposures less than the human clinical exposure based on body surface area (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
2) ABNORMAL CYCLES a) PASIREOTIDE: Abnormal cycles or acyclicity were also observed in rats administered at a dose 4-fold higher than the maximum therapeutic exposure, based on body surface area (Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
b) PASIREOTIDE DIASPARTATE: At systemic exposures 5 times higher than the maximum therapeutic exposure based on surface area, abnormal cycles or acyclicity were observed (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
3) RETARDATION OF PHYSIOLOGICAL GROWTH a) PASIREOTIDE: Retardation of physical growth was observed in rats administered 2 mg/kg/day (9-fold the maximum therapeutic dose, based on body surface area) during gestation through lactation and weaning; however, after weaning, pup weight increased comparable to controls (Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
b) PASIREOTIDE DIASPARTATE: RATS: Retardation of physiological growth in rat pups was also observed at the dose of 2 mg/kg/day (12 times higher than the maximum therapeutic dose based on surface area comparisons across species), but the effect was reversible as both weight gains were comparable to controls after weaning (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
4) MATERNAL TOXICITY a) PASIREOTIDE: Maternal toxicity was observed in rats and rabbits administered subQ doses of 1 mg/kg/day (12-fold and 5-fold higher than the maximum therapeutic dose, based on AUC, respectively) and higher throughout organogenesis (Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
b) PASIREOTIDE DIASPARTATE: RABBITS: Maternal toxicity was observed in rabbits that received 1 mg/kg/day (exposure 7 times higher than the maximum therapeutic exposure) subQ through organogenesis (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
c) PASIREOTIDE DIASPARTATE: RATS: Maternal toxicity was observed at all doses tested in embryofetal development studies in rats who received 1, 5, and 10 mg/kg/day subQ through organogenesis. The 1 mg/kg/day dose had exposures 4 times higher than that of the maximum therapeutic dose based on AUC comparisons across species. Maternal toxicity was also observed in rats who received 2 mg/kg/day (12 times higher than the maximum therapeutic dose based on surface area comparisons across species) subQ during gestation through lactation and weaning (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) BREAST MILK a) It is not known if octreotide, lanreotide, pasireotide, or pasireotide diaspartate is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drugs are unknown (Prod Info SANDOSTATIN(R) solution for injection, 2008; Prod Info SOMATULINE(R)DEPOT subcutaneous injection, 2007; Prod Info SIGNIFOR(R) subcutaneous injection, 2012; Prod Info SIGNIFOR(R) LAR intramuscular injection suspension, 2014).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) SQUAMOUS CELL CARCINOMAS 1) OCTREOTIDE: Studies in rats demonstrated a 12% incidence of squamous cell carcinomas at highest dose level of octreotide,1250 mcg/kg/day (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
B) INJECTION SITE SARCOMAS 1) OCTREOTIDE: Studies in rats demonstrated a 27% incidence of injection site sarcomas at highest dose level of octreotide,1250 mcg/kg/day (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
C) LACK OF EFFECT 1) PASIREOTIDE: Rats administered 0.01, 0.05, or 0.3 mg/kg/day (7-fold higher than the maximum recommended clinical exposure at the 1.8-mg/day dose) subQ for 104 weeks did not have drug-related tumors. No carcinogenic potential was identified in mice administered 0.5, 1, or 2.5 mg/kg/day subQ for 26 weeks (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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Genotoxicity |
A) OCTREOTIDE: No mutagenic effects can be attributed to octreotide treatment (Prod Info Sandostatin LAR(R) Depot, octreotide acetate for injectable suspension, 1998).
B) PASIREOTIDE: In vitro assays (Ames mutation test in Salmonella and E coli and mutation test in human peripheral lymphocytes) indicate pasireotide is not genotoxic. No genotoxic effects were demonstrated for pasireotide in an in vivo rat bone marrow nucleus test (Prod Info SIGNIFOR(R) subcutaneous injection, 2012).
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