Dosing and uses of Signifor, Signifor LAR (pasireotide)
Adult dosage forms and strengths
SC injection solution (Signifor)
- 0.3mg/mL
- 0.6mg/mL
- 0.9mg/mL
IM injection suspension (Signifor LAR)
- 20mg/vial
- 40mg/vial
- 60mg/vial
Cushing Disease
Indicated for treatment of adults with Cushing disease in whom pituitary surgery is not an option or has not been curative
Signifor: 0.6-0.9 mg SC BID initially; titrate dose based on response and tolerability
Dosage range: 0.3-0.9 mg SC BId
Dosage modifications (Cushing Disease)
If started on 0.6 mg BID, a dosage increase to 0.9 mg BID may be considered if treatment tolerated
Temporarily reduce dose for significant adverse effects by decrements of 0.3 mg/injection
Renal impairment: No dosage adjustment required
Hepatic impairment (Cushing Disease)
- Moderate (Child Pugh B): 0.3 mg SC BID initially; not to exceed 0.6 mg BID
- Severe (Child Pugh C): Avoid use
Acromegaly
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
Signifor LAR (initial dose): 40 mg IM q4wk
If tolerated, may increase dose to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age and sex adjusted insulin-like growth factor-1 (IGF-1) levels after 3 months of treatment with 40 mg
Dosage modifications (Acromegaly)
Renal impairment: No dosage adjustment required
Adverse effect/over-response
- Adverse reactions or over-response to treatment (age and sex adjusted IGF-1 less than the lower limit of normal) may require dose reduction
- Decrease the dose, either temporarily or permanently, by 20 mg decrements
Hepatic impairment
- Mild (Child-Pugh C): No dosage adjustment required
- Moderate (Child-Pugh B): 20 mg IM q4wk; not to exceed 40 mg q4wk
- Severe (Child-Pugh C): Avoid use
Dosing Considerations
Evaluation for treatment response is based on reduction in 24-hr urinary free cortisol levels and/or improvement in disease signs and symptoms
Maximum urinary free cortisol reduction typically seen by 2 months of treatment
Continue treatment as long as benefit is derived
Intensively optimize antidiabetic therapy (if blood glucose poorly controlled) before initiating pasireotide
Baseline tests
- Obtain the following before initiating:
- -Fasting plasma glucose
- -Hemoglobin A1c
- -Liver tests
- -Electrocardiogram
- -Gallbladder ultrasound
Administration
SC injection (Signifor)
- Visually inspect solution for particulate matter and discoloration; do not use if particulates and/or discoloration observed
- Avoid injection in sites showing signs of inflammation or irritation
- Gently pinch skin at the injection site and hold the needle/syringe at an angle of approximately 45 degrees
- Administer SC by self-injection into the top of thigh or abdomen
- Rotate injection sites; use of the same injection site for 2 consecutive injections is not recommended
IM injection (Signafor LAR)
- Remove kit from refrigerator and let it sit for at least 30 min (but not longer than 24 hr)
- Reconstitute with supplied diluent until powder is completely suspended (see package instructions)
- Insert the needle fully into the left or right gluteus at a 90° angle to the skin
- Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated)
- Slowly depress the plunger until the syringe is empty
- Withdraw the needle from the injection site and activate the safety guard
Pediatric dosage forms and strengths
Safety and efficacy not established
Signifor, Signifor LAR (pasireotide) adverse (side) effects
>10%
Diarrhea (58%)
Nausea (52%)
Hyperglycemia (40%)
Cholelithiasis (30%)
Headache (28%)
Abdominal pain (24%)
Fatigue (19%)
Diabetes mellitus (18%)
Injection site reactions (17%)
Nasopharyngitis (13%)
Alopecia (12%)
Asthenia (11%)
Increased A1c (11%)
1-10%
Increased ALT (10%)
Increased GGT (10%)
Edema, peripheral (10%)
Upper abdominal pain (10%)
Decreased appetite (10%)
Hypercholesterolemia (10%)
Hypertension (10%)
Dizziness (9%)
Hypoglycemia (9%)
Type 2 diabetes mellitus (9%)
Anxiety (9%)
Influenza (9%)
Insomnia (9%)
Myalgia (9%)
Arthralgia (8%)
Pruritus (8%)
Increased lipase (7%)
Constipation (7%)
Hypotension (7%)
Vomiting (7%)
Back pain (6%)
Dry skin (6%)
Prolonged QT interval (6%)
Hypokalemia (6%)
Pain in extremity (6%)
Sinus bradycardia (6%)
Vertigo (6%)
Abdominal distension (6%)
Adrenal insufficiency (6%)
Increased AST (6%)
Increased blood glucose (6%)
Anemia (4%)
Increased amylase (2%)
Prolonged PTT (2%)
Warnings
Contraindications
None
Cautions
Suppresses ACTH, which may lead to decreased cortisol and potential hypocortisolism; monitor for weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, or hypoglycemia
Nearly all patients develop worsening glycemia in first 2 weeks of treatment; higher risk in poorly controlled diabetics (ie, HBA1c >8%)
May cause bradycardia and QT prolongation; obtain baseline and periodic ECG, and potassium and magnesium levels; correct/supplement potassium and /or magnesium if clinically warranted
Increased liver enzymes may require dose interruption and reduction
Cholelithiasis reported; perform gallbladder ultrasound at baseline and at 6- to 12-months
Monitor for pituitary hormone deficiency (eg, TSH/free T4, GH/IGF-1)
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown whether distributed in human breast milk; excreted in rat milk at levels 30% of the plasma level; cannot exclude risk to breastfeeding children
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Signifor, Signifor LAR (pasireotide)
Mechanism of action
Cyclohexapeptide somatostatin analog; binds to human somatostatin receptors (hsst) 1, 2, 3, 4 and 5
Absorption
Peak plasma time: 0.25-.5 hr
Distribution
Protein bound: 88%
Vd: >100 L
P-gp substrate (low)
Metabolism
Since somatropin increases CYP450 enzymes, suppression of growth hormone secretion by somatostatin analogs may decrease clearance of compounds metabolized by CYP450 enzymes
Elimination
Total body clearance: 3.8 L/hr
Excretion: bile (main), renal (small)
