Pharmacological Class:
Cyclohexapeptide somatostatin analog.

Active Ingredient(s):
Pasireotide diaspartate 0.3mg/mL, 0.6mg/mL, 0.9mg/mL; soln for SC inj.

Company
Novartis Pharmaceuticals Corp

Indication(s):

Treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Pharmacology:

Pasireotide exerts its activity via binding to somatostatin receptors (ssts). Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express hsst5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

Clinical Trials:

A Phase 3, multicenter, randomized study was conducted to eva luate the safety and efficacy of two dose levels of Signifor over a 6-month treatment period in Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery.
 
Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal (ULN) were randomized to receive a Signifor dosage of either 0.6mg SC b.i.d. or 0.9mg SC b.i.d. After three months of treatment, patients with a mean 24-hour UFC ≤2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3mg b.i.d. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3mg b.i.d. at any time during the study for intolerability. The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after 6 months of therapy and did not dose increase during this period.
 
At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6mg b.i.d. and 0.9mg b.i.d. groups, respectively. The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6mg bid and 41% in the 0.9mg bid groups. Dose increases appeared to have minimal effect on 24-hour UFC response. The mean and median percentage changes in UFC from baseline were -22% and -47% in the 0.6mg b.i.d. group, and -42% and -46% in the 0.9mg b.i.d. group.

Legal Classification:

Rx

Adults:

Initially 0.6mg or 0.9mg by SC inj twice daily; usual range: 0.3mg–0.9mg twice daily. Titrate based on response and tolerability. Hepatic impairment: moderate (Child-Pugh B): initially 0.3mg twice daily; max 0.6mg twice daily; severe (Child-Pugh C): avoid.

Children:

<18years: not established.

Warnings/Precautions:

Monitor for hypocortisolism; consider temporary dose reduction, interruption or steroid replacement therapy if occurs. Diabetes: risk of hyperglycemia; initiate or adjust anti-diabetic treatment if occurs. Congenital long QT prolongation. Cardiac disease (including recent MI, CHF, unstable angina, significant bradycardia). High-grade heart block. Hypokalemia. Hypomagnesemia. Correct and monitor electrolytes prior to starting and during therapy. Hepatic impairment. Monitor baseline fasting plasma glucose, HbA1c, LFTs, ECG, gallbladder ultrasound, pituitary function prior to initiation and periodically during treatment. Pregnancy (Cat. C). Nursing mothers: not recommended.

Interaction(s)

Caution with anti-arrhythmics or other drugs that may prolong the QT interval. May antagonize cyclosporine (adjust dose). May potentiate bromocriptine; dose reduction may be needed.

Adverse Reaction(s)

Diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, diabetes; bradycardia, QT prolongation.

How Supplied:

Single-dose ampule—60

LAST UPDATED:

4/9/2013