SIGNIFOR LAR KIT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SIGNIFOR LAR KIT (SIGNIFOR LAR KIT).
Somatostatin analog that binds to somatostatin receptors (primarily sst2 and sst5), inhibiting growth hormone (GH) and insulin-like growth factor 1 (IGF-1) secretion, and reducing hormone release from neuroendocrine tumors.
| Metabolism | Metabolized by peptidases and not significantly via CYP450 enzymes. |
| Excretion | Primarily renal (approximately 85% of administered dose excreted unchanged in urine); minimal biliary/fecal excretion (less than 10%). |
| Half-life | Terminal elimination half-life following intramuscular injection of the long-acting formulation is approximately 19 days (range 15–23 days), supporting monthly dosing intervals. |
| Protein binding | Approximately 75% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Steady-state volume of distribution (Vd) is approximately 2.2 L/kg (total Vd ~200 L for a 70 kg patient), indicating extensive extravascular distribution. |
| Bioavailability | Absolute bioavailability for intramuscular injection (LAR formulation) is approximately 80% compared to subcutaneous administration; subcutaneous bioavailability is approximately 100% (reference for immediate-release formulation, but LAR is only for IM use). For the LAR kit, only IM route is relevant, with near complete release over 4 weeks. |
| Onset of Action | Administration via intramuscular injection as long-acting release: clinical effect (suppression of growth hormone and insulin-like growth factor-1) observed within 1–3 months after first injection, with maximal suppression typically by 3 months. |
| Duration of Action | Duration of clinical effect (suppression of GH/IGF-1) persists for approximately 3–4 weeks following a single intramuscular injection, consistent with monthly dosing schedule. Clinical response maintained with continued monthly administration. |
| Molecular Weight | 1047.22 |
Intramuscular injection: 40 mg every 28 days.
| Dosage form | FOR SUSPENSION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease; use with caution. |
| Liver impairment | Child-Pugh A: 40 mg every 28 days. Child-Pugh B: 20 mg every 28 days. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; higher incidence of decreased renal function, monitor renal function. |
| 1st trimester | There are no adequate and well-controlled studies in pregnant women. In animal studies, pasireotide has been shown to cause fetal harm (increased post-implantation loss, reduced fetal weight, skeletal variations) at clinically relevant doses. Use only if potential benefit justifies potential risk. |
| 2nd trimester | Same considerations as first trimester. Limited human data; animal studies indicate developmental toxicity. Use only if clearly needed. |
| 3rd trimester | Same as above. Potential for adverse effects on fetal growth and development. Avoid use unless essential. |
Clinical note
Comprehensive clinical and safety monograph for SIGNIFOR LAR KIT (SIGNIFOR LAR KIT).
| Placental transfer | In animal studies, pasireotide crossed the placenta and was detected in fetal plasma at levels approximately 10-20% of maternal plasma concentrations. Human data are lacking, but placental transfer is expected based on molecular weight and animal data. |
| Breastfeeding |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to pasireotide or any component of the formulationDecompensated liver cirrhosis (Child-Pugh class C)
| Precautions | Gallbladder abnormalities (cholelithiasis) due to inhibition of gallbladder motility and bile secretion, Hyperglycemia and hypoglycemia due to alteration of glucose metabolism, Cardiac effects including bradycardia and QT prolongation, Pituitary apoplexy in patients with pituitary tumors, Gallbladder sludge or stones require monitoring |
| Food/Dietary | No specific food restrictions. However, patients with hyperglycemia should follow diabetic dietary guidelines (low glycemic index, controlled carbohydrate intake). Avoid grapefruit juice as it may affect CYP3A4 metabolism of pasireotide. Maintain consistent meal timing to help manage blood glucose fluctuations. |
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| It is not known whether pasireotide is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from pasireotide, or from the potential tumorigenicity shown in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy category C. In animal studies, pasireotide (component of SIGNIFOR LAR KIT) caused embryotoxicity and fetal abnormalities at clinically relevant doses. In humans, limited data; risk of fetal harm cannot be ruled out. First trimester: potential teratogenic effects. Second/third trimesters: possible fetal growth restriction and metabolic disturbances due to maternal cortisol suppression. |
| Fetal Monitoring | Monitor maternal blood glucose and HbA1c for hyperglycemia/diabetes; liver function tests; serum cortisol and clinical signs of hypocortisolism; fetal growth ultrasound and amniotic fluid volume assessment due to risk of intrauterine growth restriction. Consider monitoring for QT prolongation in high-risk patients. |
| Fertility Effects | Pasireotide may suppress pituitary hormones (LH, FSH), potentially impairing fertility in both men and women. Reversible upon discontinuation. In females, may cause menstrual irregularities including amenorrhea, anovulation. |
| Clinical Pearls | Signifor LAR (pasireotide pamoate) is a somatostatin analogue with high affinity for sstr5, sstr2, and sstr3. It is approved for Cushing's disease and acromegaly. Key pearls: 1) Monitor glucose closely as hyperglycemia is a frequent AE; consider antidiabetic therapy. 2) Administer only as IM gluteal injection; do not substitute with subcutaneous pasireotide. 3) Evaluate QT interval before and during therapy; avoid with other QT-prolonging drugs. 4) Check liver function tests, bilirubin, and gallbladder ultrasound; cholelithiasis risk. 5) For Cushing's disease, titrate based on urinary free cortisol and clinical response; efficacy may take 2-3 months. |
| Patient Advice | Take exactly as prescribed; injection given by healthcare provider every 4 weeks. · Monitor blood sugar regularly; report high blood sugar symptoms (thirst, frequent urination, blurred vision). · Report symptoms of gallstones (nausea, vomiting, abdominal pain, jaundice). · Report irregular heartbeat, fainting, or dizziness (QT prolongation). · Avoid pregnancy; use effective contraception during treatment and for 3 months after last dose. · Do not drive or operate machinery if you experience dizziness or visual changes. · Keep all appointments for lab tests (glucose, liver enzymes, ECG). |