Octreotide acetate, SMS 201-995, synthetic octapeptide analogue of somatostatin, SMS-LAR

COMMON TRADE NAME(S): SANDOSTATIN(r), SANDOSTATIN LAR(r) (notice of compliance,1 June 1989; patent expires2 April 2011)

CLASSIFICATION:

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Octreotide is a synthetic somatostatin analogue with similar but more prolonged pharmacological effects.3 The long- acting release (LAR) formulation is a depot IM injection of suspended microspheres.4 Several mechanisms of actions have been suggested, including the inhibition of exocrine secretion in the digestive system (eg, gastrin, serotonin), inhibition of endocrine secretion of hormones (eg, growth hormone, insulin, glucagon), modulation of biliary and GI motility, acting as a neurotransmitter, and induction of apoptosis. Five somatostatin receptor subtypes have been identified4 in gastro-entero-pancreatic (GEP) endocrine tumours. Octreotide is used to control hormone- mediated symptoms in GEP endocrine tumours such as insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma/acromegaly, and carcinoid tumours.3 Octreotide is cell cycle phase-specific (G1- phase).3

PHARMACOKINETICS:

Octreotide LAR pharmacokinetics is similar once the drug is released from microspheres.4

SPECIAL PRECAUTIONS:

FDA Pregnancy Category B. Animal-reproduction studies have not shown a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown a fetal risk (other than decreased fertility) not confirmed in controlled studies in pregnant women in the first trimester and there is no evidence of risk in

later trimesters.5 Breastfeeding: Although octreotide is likely digested when taken orally,5 breastfeeding should be avoided unless the potential benefit justifies the potential risk to the infant.4

SIDE EFFECTS:

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Incidence derived from endocrine tumour ( *) and acromegaly (+) trials
allergy/immunology	anaphylactic and hypersensitivity reactions (rare)	I
auditory/hearing	otitis and tinnitus (0-2%)		E
cardiovascular (arrhythmia)	bradycardia and conduction abnormalities (rare)		E
cardiovascular (general)	edema (1-3%)		E
constitutional symptoms	fatigue (1 * -10 + %, severe 0.5% * )		E	D
	fever (0-2%)	I
	weight gain (0-2%)		E
dermatology/skin	extravasation hazard : none
	acne (0-4%)		E	D
	alopecia (1-4%)		E
	bruise (0.5-4%)		E
	flushing (0.5-2%)	I	E
	injection site: hematoma (0 * -10 + %), pain (8-10%)	I
	pruritus (0-4%)		E

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Incidence derived from endocrine tumour ( *) and acromegaly (+) trials
endocrine	diabetes mellitus (rare)		E
	hot flashes (0-2%)		E
	hypoadrenalism (0-3%)		E
	hypogonadism (0-2%)		E
	hypothyroidism (0-2%)		E
gastrointestinal	emetogenic potential : nonemetogenic
	abdominal: discomfort (4 * -44 + %), distention (0 * -8 + %)	I	E
	anorexia (0-2%)	I
	belching (0-2%)	I
	biliary tract abnormalities (including gallstones) (52 + -62 * %)				L
	cholecystitis (0-2%)		E
	constipation (1 * -9 + %)	I
	diarrhea (7 * -58 + %)	I
	dry mouth (0.5-2%)	I
	flatulence (0.5 * -13 + %)	I	E
	gallstones (24-22%)				L
	hemorrhoids (0-2%)		E
	nausea (9 * -30 + %)	I	E
	pancreatitis, acute (rare)	I
	pancreatitis, chronic (rare)				L
	rectal gas (0-4%)	I
	stools: abnormal (0.5 * -6 + %), loose (3 * -36 + %)	I
	stools, fatty (4-0%)	I	E
	vomiting (3-4%)	I
hemorrhage	epistaxis (0-2%)		E
hepatic	acute hepatitis (rare)		E
hepatic	hyperbilirubinemia (rare)			D	L
infection	urinary tract infection (0-6%)		E
infection	vagina infection (0-3%)		E
metabolic/laboratory	hyperglycemia (15%) 9	I
	hyperkalemia (rare) 23	I
	hypoglycemia (0-2%)	I
	decreased serum zinc levels (rare)
	decreased vitamin B 12 levels (rare)
musculoskeletal	arm/leg: heavy or tired (0-3%)		E
	arthritis (0-3%)		E
	osteoarthritis (0-2%)		E
	twitching (0-2%)		E
	vertebral disk disorder (0-2%)		E

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Incidence derived from endocrine tumour ( *) and acromegaly (+) trials
	weakness (1-0%)		E
neurology	dizziness (2 * -15 + %)		E
	irritability (0-2%)		E
	mood: anxiety (0.5-3%), depression (0.5-3%)moody (0-3%)		E
	numbness (0-2%)		E
	sleepiness/insomnia (0.5-2%)		E
ocular/visual	visual disturbances (0.5-3%)		E
pain	back pain (0.5-4%)		E
	cramps (0-3%)	I	E
	foot pain (0-2%)		E
	headache (2 * -18 + %)	I	E
	joint pain (0-4%)		E
	kidney pain (0-2%)		E
	leg: cramps (0-4%), pain (0-3%)		E
	throat pain (0.5-3%)		E
pulmonary	dyspnea (0-2%)		E
	nasal congestion (0-2%)		E
	sinusitis (0-4%)		E
renal/genitourinary	breast lump (0-2%)			D
	dysuria (0-2%)		E
	polyuria (0-2%)		E
	prostatitis (0-2%)		E
	urinary frequency (0-4%)		E
	vagina itch (0-2%)		E
secondary malignancy	breast tumour (0-2%)			D
syndromes	flu-like symptoms (0-6%)	I

Adapted from reference 4 unless otherwise specified.

Biliary tract abnormalities

such as gallstones, sludge without stones and biliary duct dilatation, may occur after more than 12 months of therapy. Only 1% of patients becomes symptomatic and requires intervention. Patients on

long-term octreotide should be assessed with ultrasound of the gallbladder and bile ducts every 6-12 months.4 Gallstones usually respond to chenodeoxycholic acid or ursodeoxycholic acid. Interruption or discontinuation of octreotide may be considered based on the risk-benefit ratio of the patient.9 GI side effects may be reduced by giving SC injections between meals or at bedtime.4 GI side effects with octreotide LAR are mild to moderate, often disappear within 1-4 days of injection, and decrease with long term treatment.9 Note that diarrhea in patients with carcinoid syndrome may be due to excessive hormone secretion or other causes and should be treated according to etiology.3

Injection site reactions 4

after SC injection include pain, stinging, tingling or burning, and rarely, redness, swelling or rash. They usually last less than 15 minutes for SC injections or 60 minutes for LAR injections. Local discomfort may be reduced by allowing the solution to reach room temperature before injection and by injecting slowly.

BCCA Cancer Drug Manual(c) 2001 Page 4 of 8 Octreotide Hyperglycemia is usually transient and mild.9,24 Reduced glucose tolerance may be due to imbalance between insulin, glucagon and growth hormone. Post prandial blood sugar may be increased in nondiabetics and type II diabetics. Patients should be observed more closely when starting octreotide or changing doses.4

Malabsorption

of dietary fats and vitamin B12 has been seen. There is no evidence that long-term treatment with SC octreotide has led to nutritional deficiency due to malabsorption. It is suggested that periodic quantitative 72- hour fecal fat and serum carotene determinations be performed to aid in the assessment of possible drug-induced

aggravation of fat malabsorption. Depressed vitamin B12 levels and abnormal Schilling's tests have been observed, and monitoring of vitamin B12 levels is recommended during therapy with octreotide LAR.4

INTERACTIONS:

No significant interactions reported with chemotherapy, H2-antagonists, antimotility drugs, hypoglycemic drugs, fluid electrolyte or hyperalimentation solutions, antihypertensive diuretics and antidiarrheal drugs. Octreotide may reduce cytochrome P450 (CYP) 3A4 metabolism of drugs by suppression of growth hormone. Drugs metabolized mainly by CYP 3A4 and with low therapeutic

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on solution preparation and compatibility, see Chemotherapy Chart in Appendix.

50 mcg/mL, 100 mcg/mL or 500 mcg/mL of SC octreotide ampules; 200 mcg/mL (5 mL vial) of SC octreotide multidose vials; 10 mg, 20 mg or 30 mg of octreotide LAR vials with two vehicle ampules. For prolonged storage, keep under refrigeration. Avoid freezing of SC multidose vials. For day-to-day use, ampules and SC multidose vials may be stored at room temperature for up to 2 weeks. LAR vials can remain at room temperature on the day of injection but the suspension should be prepared immediately before administration. Do not use heat to

bring solution rapidly to room temperature, as octreotide may be damaged. Protect from light. Discard unused portion of SC ampules.4 Reconstitute octreotide LAR powder: Allow octreotide LAR and vehicle vials to warm at room temperature for 30- 60 minutes.8 Suspend powder with 2 mL of vehicle immediately before injection. Each kit contains a reserve vehicle ampule. Without disturbing the powder, gently inject the vehicle into the vial by running the it down the inside wall of the vial. Withdraw any excess air from the vial. Do not disturb the vial until the vehicle has wetted the powder. Once complete wetting has occurred (about 2-5 minutes), the vial should be moderately swirled until a uniform suspension is achieved. Do not shake the vial vigorously. Slowly withdraw the entire vial contents into the syringe. Immediately change the needle (supplied). Gently invert the syringe as needed to maintain a uniform suspension.4

For continuous IV infusion, dilute octreotide SC solution in NS. Stable for 24 hours at room temperature. Discard unused portion. Reconstituted octreotide LAR suspension must never be given IV.

One study reported that octreotide retained its potency for 30 days when stored in Travenol, Minimed and Becton-Dickinson (Plastipak) plastic syringes of polypropylene and natural rubber. Another study, using Becton-Dickinson tip caps and polypropylene syringes, recommended a maximum storage time of one week at room temperature, whether protected from light or not. A third study, using Terumo polypropylene syringes sealed

with a cap, found losses of 6% after 60 days when stored refrigerated or frozen.25

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.

Adults: Cycle Length: BCCA usual dose noted in bold, italics Subcutaneous: Daily4: start at 50 mcg SC once or twice daily; titrate dose for maintenance based on response (eg, 150 mcg [range 50- 2000 mcg20] SC three times daily) starting dose may be higher depending on severity of symptoms acromegaly maximum dose: 1500 mcg per day4 PRN: 100 mcg SC for 2 doses, 15 min and 6 h after chemotherapy29

can be started the day after the last dose of octreotide SC. carcinoid tumours and VIPomas: Continue octreotide SC for at least two weeks in the same dose as before the switch. Some patients may require 3-4 weeks of such therapy. 10 mg starting dose not recommended as therapeutic levels reached more rapidly with a 20 mg dose For exacerbation of symptoms, give octreotide SC for a few days at the same dose as prior to switch to octreotide LAR. When symptoms are controlled, octreotide SC can be discontinued.

carcinoid tumours and VIPomas: octreotide SC: at least 2 weeks, then switch "responders" to octreotide LAR4

in patients with cirrhosis, the half-life of the drug may increase and adjustment

Interpatient variability	no information found
Absorption	SC: rapidly and completely absorbed; LAR injection: steady state after 2-3 injections at 4- weekly intervals, 4 which is chosen to cover escape between days 21 and 42 3
	time to peak plasma concentration	SC: 30 min; LAR injection: level peaks at 1 hour, then becomes subtherapeutic for 7 days before increasing to plateau at day 14 for 3-4 weeks
Distribution	mainly in liver, kidneys, skin and lungs; 4 crosses human placenta to fetus. 5
	cross blood brain barrier?	no information found
	volume of distribution	0.4 L/kg
	plasma protein binding	65%
Metabolism	30-40% metabolized in the liver 6
	active metabolite(s)	none
	inactive metabolite(s)	peptide fragments 7
Excretion	renal 8
	urine	11-32% as unchanged drug 9
	feces	mainly unchanged drug
	terminal half life	SC: 100 min; IV: 90 min
	clearance	160 mL/min 4 ; acromegaly 300 mL/min; chronic renal failure 75 mL/min 9
Gender	no information found
Elderly	no information found
Children	no information found
Ethnicity	no information found

Primary uses:	Other uses:
* Acromegaly 10-13	Chemotherapy-induced diarrhea 14,15
* Carcinoid syndrome 16-18	Malignant intestinal obstruction 6
* VIPomas 19	Pancreatic cancer 20
Gastro-entero pancreatic (GEP) endocrine tumours 3	Thymoma 21,22

AGENT	EFFECT	MECHANISM	MANAGEMENT
bromocriptine	increased bromocriptine bioavailability	unknown	adjust bromocriptine dose as needed
cimetidine	delayed cimetidine absorption	altered GI absorption of cimetidine	adjust cimetidine dose as needed
cyclosporine	delayed absorption and decreased serum cyclosporine levels	altered GI absorption of cyclosporine	monitor serum cyclosporine levels; adjust cyclosporine dose as needed

BCCA administration guideline noted in bold , italics
Subcutaneous	in the smallest volume that will deliver the dose Rotate injection sites. 25 Local discomfort may be reduced by allowing the solution to reach room temperature before injection and by injecting slowly. Do not use heat to bring solution rapidly to room temperature. 4
Intramuscular (for octreotide LAR)	by deep intragluteal injection Alternate between left and right gluteal muscles. If a blood vessel is penetrated, select another injection site. Do not use heat to bring solution rapidly to room temperature. 4 May use quadriceps for self-administration. 26
Direct intravenous Octreotide LAR must never be given IV.	IV over 15 seconds - 3 min 25,27 for emergency situations only 8
Intermittent infusion Octreotide LAR must never be given IV.	in 50 mL NS over 15-30 min infusion rate must be controlled by an automated infusion control device. 27
Continuous infusion Octreotide LAR must never be given IV.	infuse at 25-50 mcg/h 27
Intraperitoneal	no information found
Intrapleural	no information found
Intrathecal	investigational, 5-10 mcg/h for severe intractable nonmalignant pain 28
Intra-arterial	no information found
Intravesical	no information found

SYNONYM(S):