Pasireotide (Signifor) is synthetic long-acting somatostatin like a drug. It is an orphan drug in the US and Europe used in the treatment of Cushing's disease and acromegaly.

Indications of Pasireotide:

• Acromegaly (Signifor LAR):

  • It is 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.
  • The Endocrine Society suggests the use of a somatostatin analog is advised before surgery in selected patients to reduce surgical risk from severe comorbidities.
  • It is also given as initial adjuvant therapy in patients with persistent, significant disease (ie, moderate to severe signs and symptoms of growth hormone excess and without local mass effects).
  • Patients with mild disease are treated with alternative agents postoperatively.

• Cushing disease (Signifor and Signifor LAR):

  • It is used for the treatment of Cushing disease in patients for whom pituitary surgery is not an option or has not been curative.

Pasireotide dose in adults:

The treatment dose of Pasireotide in Patients with Acromegaly (Signifor LAR):

• Initial: 40 mg intramuscular once every 28 days;
• For patients who have not normalized GH and/or IGF-1 levels after 3 months, the dose may be increased to a maximum of 60 mg once every 28 days.
• Dose reduction by 20 mg decrements is necessary if adverse reactions occur or IFG-1 level decreases to less than the lower limit of normal.
• Missed dose:
  • If a dose is missed, the dose may be given up to but no later than 14 days before the next dose.

Pasireotide dose in the treatment of Cushing disease:

• Signifor:

  • Initial: 0.6 mg or 0.9 mg subcutaneous b.i.d daily.
  • Titrate based on response and tolerability.
  • Temporarily decrease dose by 0.3 mg increments in case of adverse effects.
  • Recommended maintenance dosage range:
    • 0.3 to 0.9 mg subcutaneous b.i.d daily.

Note: Maximum urinary free cortisol reductions are usually observed by 2 months of treatment.

• Signifor LAR:

  • Initial: 10 mg intramuscular once every 28 days;
  • for patients who have not normalized 24-hour urinary free cortisol after 4 months, the dose may be increased.
  • The maximum dose is 40 mg once every 28 days.
  • Interruption of therapy or dose reduction is required in case adverse reactions or decrease in cortisol level to less than the lower limit of normal or is in the lower normal range in patients with symptoms suggestive of adrenal insufficiency.
  • Missed dose:
    • If a dose is missed, the dose may be given up to but no later than 14 days before the next dose.

Use in children:

The efficacy and safety of the drug in children have not been established.

Dose in pregnancy and lactation:

• Alternate agents should not be used during pregnancy to treat acromegaly.
• During pregnancy, monitoring of insulin-like growth factor 1 (IGF-1) and/or growth hormone(GH) is not recommended, as an active placental GH variant present in maternal blood limits the usefulness of the results.
• Females with Cushing disease can be treated to improve their fertility by achieving a normal serum cortisol level and normalizing IGF-1 and GH levels in women with acromegaly.
• According to the Endocrine Society, women should not use effective contraception during treatment.
• They should also stop using long-acting somatostatin analogues 2 months before they plan to have a baby.
• If necessary, short-acting octreotide can be used up to conception.

Pasireotide use during breastfeeding:

• Pasireotide excretion is not known in breast milk.
• According to the manufacturer the decision to breastfeed during therapy is based on the risks/benefits to the infant and the benefits to the mother.

Pasireotide Dose adjustment in renal disease:

No dosage adjustment is necessary.

Pasireotide Dose adjustment in liver disease:

Acromegaly (Signifor LAR):

• Prior to initiation:

  • Mild impairment (Child-Pugh class A):

    • No dosage adjustment necessary.

  • Moderate hepatic impairment (Child-Pugh class B):

    • Initial: 20 mg once every 28 days.
    • maximum: 40 mg once every 28 days.

  • Severe hepatic impairment (Child-Pugh class C):

    • Avoid use.

• During therapy:

  • Permanently discontinue therapy if signs/symptoms of clinically significant hepatic impairment occur.

Cushing disease:

• Signifor:

  • Prior to initiation:

    • Mild impairment (Child-Pugh class A):

      • No dosage adjustment is necessary.

    • Moderate impairment (Child-Pugh class B):

      • Initial: 0.3 mg twice daily.
      • maximum: 0.6 mg twice daily.

    • Severe impairment (Child-Pugh class C):

      • Use not recommended.

  • During therapy:

    • If ALT increases >3 times ULN or baseline value:

      • Recheck ALT during the recommended time frame per recommendations in the manufacturer's labeling for confirmation.
      • Therapy should be stopped and workup should be done to find the cause in case of rising ALT level.

    • If any liver test ≥5 times ULN (with a normal baseline) OR >5 times the baseline value (with an abnormal baseline):

      • The manufacturer recommends stopping therapy and monitoring liver tests more frequently.
      • Therapy can be restarted with caution if values return to normal.

• Signifor LAR:

  • Prior to initiation:

    • Mild impairment (Child-Pugh class A):

      • No dosage adjustment is necessary.

    • Moderate hepatic impairment (Child-Pugh class B):

      • Initial: 10 mg once every 28 days.
      • maximum: 20 mg once every 28 days.

    • Severe hepatic impairment (Child-Pugh class C):

      • Avoid use.

  • During therapy:

    • Therapy should be permanently stopped in case of clinically significant hepatic impairment occur.

Common Side Effects of Pasireotide:

• Cardiovascular:

  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Fatigue
  • Hypertension
  • Insomnia
  • Anxiety

• Dermatologic:

  • Alopecia

• Endocrine & Metabolic:

  • Hyperglycemia
  • Diabetes Mellitus
  • Hypoglycemia
  • Increased Gamma-Glutamyl Transferase
  • Hypercholesterolemia

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Cholelithiasis
  • Increased Serum Lipase
  • Abdominal Pain
  • Increased Serum Amylase
  • Upper Abdominal Pain
  • Abdominal Distension
  • Decreased Appetite

• Hematologic & Oncologic:

  • Prolonged Partial Thromboplastin Time
  • Prolonged Prothrombin Time
  • Elevated Glycosylated Hemoglobin

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase

• Infection:

  • Influenza

• Local:

  • Injection Site Reactions

• Neuromuscular & Skeletal:

  • Asthenia
  • Increased Creatine Phosphokinase In Blood Specimen
  • Myalgia
  • Back Pain

• Respiratory:

  • Nasopharyngitis

Rare Side Effects Of Pasireotide:

• Cardiovascular:

  • Sinus Bradycardia
  • Hypotension
  • Atrioventricular Block
  • Prolonged Q-T Interval On ECG

• Central Nervous System:

  • Dizziness
  • Vertigo

• Dermatologic:

  • Pruritus
  • Xeroderma

• Endocrine & Metabolic:

  • Hyperuricemia
  • Hypokalemia
  • Adrenocortical Insufficiency
  • Decreased Cortisol
  • Weight Loss
  • Impaired Glucose Tolerance/Prediabetes
  • Hypothyroidism

• Gastrointestinal:

  • Vomiting
  • Constipation
  • Flatulence
  • Cholestasis
  • Cholecystitis
  • Pancreatitis

• Hematologic & Oncologic:

  • Anemia

• Neuromuscular & Skeletal:

  • Arthralgia
  • Limb Pain

• Respiratory:

  • Upper Respiratory Tract Infection
  • Cough

Contraindications to Pasireotide:

• Hypersensitivity to pasireotide and any component of the formulation
• Bradycardia severe
• Sick sinus syndrome
• Congenital long QT syndrome
• AV block (second/third degree), Sinoatrial block
• NYHA Class III and IV Heart Failure
• Cardiogenic shock
• Uncontrolled DM (HbA >=8%), despite therapy
• Moderate to severe hepatic impairment (Child Pug B or C).

Warnings and precautions

• Cardiac disorders:

  • Pasireotide may cause bradycardia or QT prolongation.
  • Bradycardia is caused by high-grade heart disease, history of bradycardia and concomitant use of drugs that can cause it.
  • QT prolongation is possible due to congenital long QT, congenital heart failure, unstable angina or hypokalemia as well as concomitant use of drugs known to prolong QT.
  • It is important to monitor your ECG frequently before and during treatment.
  • Before treatment, it is important to correct hypokalemia, hypomagnesemia or hypocalcemia.
  • Patients with a history of heart disease should not use it.

• Cholelithiasis

  • Cholelithiasis can be caused by therapy and may result in complications such as cholecystitis (cholangitis), pancreatitis, and cholecystitis.
  • Cholelithiasis should be monitored regularly and the therapy should be stopped.

• Hepatic effects

  • Pasireotide can cause liver enzyme derangement.
  • It is important to monitor your condition regularly and stop any therapy if you have severe impairments.

• Hyperglycemia/diabetes:

  • Inhibition of insulin or glucagon can cause hyperglycemia.
  • Hyperglycemia can be diagnosed with first therapy. It can also progress to diabetes or prediabetes.
  • Poor baseline glycemic control increases the risk.
  • Before therapy, fasting blood glucose and hemoglobin A1c levels (HbA) should be checked. Antidiabetic therapy should also be optimized for diabetic patients with poor baseline control.
  • It is important to monitor blood glucose levels during therapy, particularly after an increase in dose.
  • Hyperglycemia is a good time to start antidiabetic treatment.
  • Persistent hyperglycemia can be treated with dose reduction or discontinuation.

• Hypocortisolism

  • Hypocortisolism can occur in Cushing disease if the Adrenocorticotropic Hormone (ACTH) is suppressed.
  • Hypocortisolism symptoms such as nausea, vomiting and weakness, hyponatremia, hypotension, and hypoglycemia should be monitored.
  • In the event of severe symptoms, it is important to reduce or stop therapy.
  • Temporary replacement therapy with glucocorticoid may be necessary.

• Hypothyroidism:

  • Thyroid function can be affected by Pasireotide. Therefore, it is important to monitor your thyroid function during and after treatment.

• Pituitary hormone deficiency (anterior):

  • Pasireotide can cause anterior pituitary hormone inhibition.
  • It is important to monitor for pituitary deficiencies, including thyroid, adrenal, and gonadal functions, before and after therapy.
  • Patients who have had transsphenoidal surgery or pituitary radiation are at greater risk.

• Diabetes:

  • It is important to optimize the antidiabetic treatment in patients with poorly controlled DM before beginning pasireotide. This is because it can often cause hyperglycemia.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious.
  • Dose reduction is required for patients with moderate impairment (Child Puugh class B).
  • It should not be done if there is severe impairment (Child Puugh class C).

Pasireotide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Acromegaly (Signifor LAR):

• Blood glucose fasting and random) and glycosylated hemoglobin
• Serum magnesium and potassium
• Thyroid function tests
• Adrenal function/ gonadal function
• pulse in patients with bradycardia or cardiac disease
• ECG monitoring
• Serum GH and IGF-1 (at 3 months prior to dosage adjustment)
• signs and symptoms of adrenal insufficiency
• Periodic monitoring for cholelithiasis.
• Liver function tests:
  • Prior to initiation, after the first 2 to 3 weeks, then monthly for 3 months and as clinically indicated; during therapy, discontinue if clinically significant liver impairment develops and monitor liver function until resolution.

Cushing disease:

• Blood glucose and HbA1C
• Serum potassium and magnesium
• Thyroid function tests
• Urinary free cortisol (24-hour)
• serum GH and IGF-1 (baseline then periodically)
• ECG (baseline and consider continued monitoring during treatment);
• gall bladder ultrasonography (baseline, then every 6 to 12 months during therapy)
• Signs and symptoms of hypocortisolism including pulse, nausea, vomiting, weakness, fatigue, nausea, vomiting

• Liver function tests:

  • Signifor: SHould be checked before therapy, 1 to 2 weeks after initiation, then monthly for 3 months, then every 6 months thereafter
  • more frequent testing may be necessary:

  • If ALT normal at baseline and ALT increases 3 to 5 times ULN on therapy:

    • Repeat ALT within 1 week

  • If ALT normal at baseline and ALT increases >5 times ULN on therapy:

    • Repeat ALT within 48 hours

  • If ALT abnormal at baseline and ALT increases 3 to 5 times baseline values on therapy:

    • Repeat ALT within 1 week

  • If ALT abnormal at baseline and ALT increases >5 times ULN on therapy:

    • Repeat ALT <1 week

Note:

• ALT levels should be done in a laboratory capable of same-day results.
• Therapy should be stopped if ALT levels are rising.
• Therapy should be stopped if any liver test ≥5 times ULN (with a normal baseline) OR >5 times the baseline value (with an abnormal baseline)and monitoring of ALT, AST, alkaline phosphatase, and total bilirubin more frequently is required.
• Therapy can be restarted with caution if values return to normal or near normal.

Signifor LAR:

• LFTs should be checked before treatment, after the first 2 to 3 weeks, then monthly for 3 months and as clinically indicated. If significant liver impairment develops, therapy should be stopped and liver function monitoring should be done.

How to administer Pasireotide?

Intramuscular:

• Signifor LAR: It should be injected into the left or right gluteus immediately after reconstitution.

SubQ:

• Signifor: It should be injected into the top of the thigh or abdomen (excluding the navel and waistline).
• It should not be injected in inflamed or irritated skin. Alternate the injection site.

Mechanism of action of Pasireotide:

• Pasireotide, a cyclohexapeptide-somatostatin analogue, is a inhibitor of multiple endocrine and neuroendocrine mechanisms.
• Cushing disease patients experience an inhibition in ACTH secretion, which results in decreased cortisol production by binding to the somatostatin receptor (sst 1-5) with high affinity for the subtypes sst-1, sst-2, and sst-3, and the highest affinity for subtype sst-5.
• Pasireotide reduces GH and IGF-1 in patients suffering from acromegaly by binding to sst-2 or sst-5.

Protein binding: 88%

Metabolism: Primarily eliminated as unchanged drug hepatically (via biliary excretion)

Half-life elimination: Subcutaneous: 12 hours

Time to peak, plasma: Subcutaneous: 0.25 to 0.5 hours

Excretion:

• Feces (40% to 56%, primarily as unchanged drug)
• urine (6% to 10%, primarily as unchanged drug)

International Brands of Pasireotide:

• Signifor
• Signifor LAR
• Signifor Liam

Pasirotide Price in the US:

Solution (Signifor for Subcutaneous administration):

each ml of 0.3 mg/mL: $279.06 each ml of 0.6 mg/mL: $279.06 each ml of 0.9 mg/mL: $279.06

Suspension Reconstituted ER (Signifor LAR Intramuscular):

Each 10 mg: $15,670.08 Each 20 mg: $15,670.08 Each 30 mg: $15,670.08 Each 40 mg: $15,670.08 Each 60 mg: $15,670.08

Pasireotide Brand Names in Pakistan:

No Brands Available in Pakistan.