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Leuprolide  (lupron ®)

Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years.

Leuprolide acetate is not active when given orally.

Dosing (Adults):
Advanced prostatic carcinoma:
Eligard®: 7.5 mg monthly or 22.5 mg every 3 months or 30 mg every 4 months
Lupron®: 1 mg/day
Viadur®: 65 mg implanted subcutaneously every 12 months

Lupron Depot®: 7.5 mg/dose given monthly (every 28-33 days) or
Lupron Depot-3®: 22.5 mg every 3 months or
Lupron Depot-4®: 30 mg every 4 months

Endometriosis: I.M.: Initial therapy may be with leuprolide alone or in combination with norethindrone; if retreatment for an additional 6 months is necessary, norethindrone should be used. Retreatment is not recommended for longer than one additional 6-month course.
Lupron Depot®: 3.75 mg/month for up to 6 months or
Lupron Depot-3®: 11.25 mg every 3 months for up to 2 doses (6 months total duration of treatment)

Uterine leiomyomata (fibroids): I.M. (in combination with iron):
Lupron Depot®: 3.75 mg/month for up to 3 months or
Lupron Depot-3®: 11.25 mg as a single injection

Eligard®: Packaged in two syringes; one contains the Atrigel® polymer system, and the second contains leuprolide acetate powder; follow instructions for mixing; must be administered within 30 minutes of mixing.
Lupron Depot®: Do not use needles smaller than 22 gauge; reconstitute only with diluent provided
Viadur® implant: Requires surgical implantation and removal at 12-month intervals
Implant (Viadur®): 65 mg [released over 12 months; packaged with administration kit]

Injection, solution, as acetate (Lupron®): 5 mg/mL (2.8 mL) [contains benzyl alcohol; packaged with syringes and alcohol swabs]
Injection, powder for reconstitution, as acetate [depot formulation; prefilled syringe]:

7.5 mg [released over 1 month]
22.5 mg [released over 3 months]
30 mg [released over 4 months]

Lupron Depot®: 3.75 mg, 7.5 mg [released over 1 month; contains polysorbate 80]
Lupron Depot®-3 Month: 11.25 mg, 22.5 mg [released over 3 months; contains polysorbate 80]
Lupron Depot®-4 Month: 30 mg [released over 4 months; contains polysorbate 80]
Lupron Depot-Ped®: 7.5 mg, 11.25 mg, 15 mg [released over 1 month; contains polysorbate 80]

Mifepristone - korlym ® 

Drug UPDATESKorlym ® (mifepristone) 300 mg Tablets
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2012

Mechanism of Action: Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.

Korlym (mifepristone) is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.

Important Limitations of Use
Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.

Administer once daily orally with a meal.
The recommended starting dose is 300 mg once daily.
Renal impairment: do not exceed 600 mg once daily.
Mild-to-moderate hepatic impairment: do not exceed 600 mg once daily. Do not use in severe hepatic impairment.

Based on clinical response and tolerability, the dose may be increased in 300 mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day.
300 mg tablet

Pregnancy (4.1, 8.1)
Use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range (4.2)
Concurrent long-term corticosteroid use (4.3)
Women with history of unexplained vaginal bleeding (4.4)
Women with endometrial hyperplasia with atypia or endometrial carcinoma (4.4)

Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency (5.1).
Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment (5.2).
Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy (5.3).
QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval (5.4).
Use of Strong CYP3A Inhibitors: Concomitant use can increase mifepristone plasma levels significantly. Use only when necessary and limit mifepristone dose to 300 mg (5.6).

Octreotide (sandostatin ® )

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 acetate has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).

Octreotide acetate substantially reduces growth hormone and/or IGF-I (somatomedin C) levels in patients with acromegaly.

Single doses of octreotide acetate have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials the incidence of gallstone or biliary sludge formation was markedly increased.

Octreotide acetate suppresses secretion of thyroid stimulating hormone (TSH).

Somatostatin analog.
Dosing (Adults)
Bleeding esophageal varices: IV bolus: 25-50 mcg followed by continuous IV infusion of 25-50 mcg/hour.

Carcinoid tumors: Initial: 50 mcg IV/SQ qd-bid. Titrate dose based on response/tolerance. Range: 100-600 mcg/day in 2-4 divided doses - usual range 50-1500 mcg/day.
VIPomas: Initial 2 weeks: 200-300 mcg/day IV/SQ in 2-4 divided doses. Titrate dose based on response/tolerance. Range: 150-750 mcg/day (doses >450 mcg/day are rarely required).

Diarrhea: Initial: 50-100 mcg IV q8h - increase by 100 mcg/dose at 48-hour intervals. Maximum dose: 500 mcg q8h.

In another prospective trial [10], a high-dose continuous infusion of octreotide acetate (100-150 µg/h) was used by Petrelli et al. in 16 patients with colorectal carcinoma and 5-FU-induced severe diarrhea who had failed to respond to conventional therapy with diphenoxylate atropine. Complete resolution of diarrhea was observed in 15 of 16 patients (94%). However, recurrence of diarrhea was seen in two patients after a complete cycle of octreotide. The authors also reported an absence of toxicity and no adverse effects of the treatment.

In a phase I trial by Wadler et al. [13], octreotide was administered in 35 patients with 5-FU-induced diarrhea to determine the maximum tolerated dose. The doses of octreotide studied were 50 to 2,500 µg administered s.c. three times daily for five days. The authors reported that the efficacy of the treatment correlated significantly (p < 0.01) with the dose of octreotide administered. Furthermore, patients experienced significant toxicities, including hypoglycemia and allergic reaction, which argued against the administration of higher doses.

The current trial has demonstrated a statistically significant benefit in the management of 5-FU-induced diarrhea in favor of the 500 µg regimen versus 100 µg octreotide administered s.c. three times per day. These results are in support of the dose-response effect of octreotide acetate.

13. Wadler S, Haynes H, Wiernik PH. Phase I trial of the somatostatin analogue octreotide acetate in the treatment of fluoropyramidine-induced diarrhea. J Clin Oncol 1995;13:222-226.

Adults: SubQ: Initial: 50 mcg 1-2 times/day and titrate dose based on patient tolerance and response

Carcinoid: 100-600 mcg/day in 2-4 divided doses

VIPomas: 200-300 mcg/day in 2-4 divided doses

Diarrhea: Initial: I.V.: 50-100 mcg every 8 hours; increase by 100 mcg/dose at 48-hour intervals; maximum dose: 500 mcg every 8 hours

Esophageal varices bleeding: I.V. bolus: 25-50 mcg followed by continuous I.V. infusion of 25-50 mcg/hour

Acromegaly: Initial: SubQ: 50 mcg 3 times/day; titrate to achieve growth hormone levels <5 ng/mL or IGF-I (somatomedin C) levels <1.9 U/mL in males and <2.2 U/mL in females; usual effective dose 100 mcg 3 times/day; range 300-1500 mcg/day

Note: Should be withdrawn yearly for a 4-week interval in patients who have received irradiation. Resume if levels increase and signs/symptoms recur.

Acromegaly, carcinoid tumors, and VIPomas (depot injection): Patients must be stabilized on subcutaneous octreotide for at least 2 weeks before switching to the long-acting depot: Upon switch: 20 mg I.M. intragluteally every 4 weeks for 2-3 months, then the dose may be modified based upon response
Dosage adjustment for acromegaly: After 3 months of depot injections the dosage may be continued or modified as follows:
GH </= 2.5 ng/mL, IGF-1 is normal, symptoms controlled: Maintain octreotide LAR® at 20 mg I.M. every 4 weeks

GH >2.5 ng/mL, IGF-1 is elevated, and/or symptoms uncontrolled: Increase octreotide LAR® to 30 mg I.M. every 4 weeks

GH </= 1 ng/mL, IGF-1 is normal, symptoms controlled: Reduce octreotide LAR® to 10 mg I.M. every 4 weeks
Dosages >40 mg are not recommended

Dosage adjustment for carcinoid tumors and VIPomas: After 2 months of depot injections the dosage may be continued or modified as follows:
Increase to 30 mg I.M. every 4 weeks if symptoms are inadequately controlled.
Decrease to 10 mg I.M. every 4 weeks, for a trial period, if initially responsive to 20 mg dose.
Dosage >30 mg is not recommended.


Injection, microspheres for suspension, as acetate [depot formulation] (Sandostatin LAR®): 10 mg, 20 mg, 30 mg [with diluent and syringe]

Injection, solution, as acetate (Sandostatin®): 0.05 mg/mL (1 mL); 0.1 mg/mL (1 mL); 0.2 mg/mL (5 mL); 0.5 mg/mL (1 mL); 1 mg/mL (5 mL)

Pasireotide - signifor® injection

DrugSIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action: SIGNIFOR LAR is an injectable cyclohexapeptide, somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTR). There are five known human somatostatin receptor subtypes: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogs bind to SSTRs with different potencies. Pasireotide binds with high affinity to four of the five SSTRs

INDICATIONS AND USAGE:   SIGNIFOR LAR is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

HOW SUPPLIED: SIGNIFOR LAR for injectable suspension: 20 mg, 40 mg, and 60 mg, powder in a vial to be reconstituted with the provided 2mL diluent.

SIGNIFOR is a somatostatin analog indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Safety and effectiveness of SIGNIFOR in children under 18 years have not been established

Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice a day; recommended dosage range is 0.3 mg to 0.9 mg twice a day.

Titrate dosage based on treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) and/or improvements in signs and symptoms of disease] and tolerability.

Testing Prior to Dosing: fasting plasma glucose, hemoglobin A1c, liver tests, electrocardiogram (ECG), and gallbladder ultrasound.

Patients with Hepatic Impairment:
? Child Pugh B: Recommended initial dosage is 0.3 mg twice a day and maximum dosage is 0.6 mg twice a day.
? Child Pugh C: Avoid use in these patients.

Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose ampule

Hypocortisolism: Decreases in circulating levels of cortisol may occur resulting in biochemical and/or clinical hypocortisolism. SIGNIFOR dose reduction or interruption and/or adding a low-dose short-term glucocorticoid may be necessary.

Hyperglycemia and Diabetes (occurs with initiation): Intensive glucose monitoring is recommended and may require initiation or adjustment of anti-diabetic treatment.

Bradycardia and QT Prolongation: Use with caution in at-risk patients; ECG testing prior to dosing and on treatment.

Liver Test Elevations: Evaluate liver tests prior to and during treatment .

Cholelithiasis: Perform gallbladder ultrasounds before starting treatment and at 6-month intervals.

Vasopressin  (pitressin ® )

ADH analog (Posterior pituitary hormone).
The antidiuretic action of vasopressin is ascribed to increasing reabsorption of water by the renal tubules.

Vasopressin can cause contraction of smooth muscle of the gastrointestinal tract and of all parts of the vascular bed, especially the capillaries, small arterioles and venules with less effect on the smooth musculature of the large veins. The direct effect on the contractile elements is neither antagonized by adrenergic blocking agents nor prevented by vascular denervation.

Following subcutaneous or intramuscular administration of vasopressin injection, the duration of antidiuretic activity is variable but effects are usually maintained for 2-8 hours.

The majority of a dose of vasopressin is metabolized and rapidly destroyed in the liver and kidneys. Vasopressin has a plasma half-life of about 10 to 20 minutes. Approximately 5% of a subcutaneous dose of vasopressin is excreted in urine unchanged after four hours.

Vasopressin is indicated for prevention and treatment of postoperative abdominal distention, in abdominal roentgenography to dispel interfering gas shadows, and in diabetes insipidus.

Dosing (Adults)
Diabetes insipidus
: Note: Dosage is highly variable - titrated based on serum and urine sodium and osmolality in addition to fluid balance and urine output. 5-10 units IM/SQ 2-4 times daily as needed (dosage range 5-60 units/day). Abdominal distention: 5 units IM stat, then 10 units every 3-4 hours.

GI hemorrhage: Continuous IV infusion: 0.5 milliunits/kg/hour (0.0005 unit/kg/hour). Double dosage as needed every 30 minutes to a maximum of 10 milliunits/kg/hour.
IV: Initial: 0.2-0.4 unit/minute, then titrate dose as needed. If bleeding stops, continue at same dose for 12 hours, taper off over 24-48 hours.
Out-of-hospital asystole
(unlabeled use): Adults: 40 units IV. If spontaneous circulation is not restored in 3 minutes, then repeat dose.
Pulseless VT/VF
: 40 units IV (as a single dose only). If no IV access - administer 40 units diluted with NS (to a total volume of 10 ml) endotracheally.

Vasodilatory shock/septic shock: Vasopressin may be used in patients with refractory shock despite adequate fluid resuscitation and the use of high-dose conventional catecholamines such as norepinephrine and dopamine, however, further studies are needed to determine its exact place in therapy. Current evidence does not support the use of vasopressin as a replacement for norepinephrine or dopamine as a first-line agent.

The recommended infusion rate for vasopressin in the treatment of shock in adults is 0.01– 0.04 units/min. This dosage range is reported to be effective in about 85% of patients with norepinephrine resistant hypotension. Doses greater than 0.04 units/min may lead to cardiac arrest.

 O'Brien A et al reported rapid rebound hypotension as a common problem after treatment with vasopressin is stopped. Potential side effects of vasopressin infusion range from ischemic skin lesions to possible intestinal ischemia. Vasopressin therapy may also result in decreased cardiac output and hepatosplanchnic flow.

Injection, solution: 20 units/mL (0.5 mL, 1 mL, 10 mL)
Pitressin®: 20 units/mL (1 mL)




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Other endocrine type agents