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Pasireotide

Also known as Signifor, Signifor LAR, SOM230, pasireotide diaspartate, pasireotide pamoate

Second-generation somatostatin analogue for Cushing's disease and acromegaly, with a strong hyperglycaemia signal.

clinically proven Hormonal & sexual approved drug

At a glance

Category
Hormonal & sexual
Status
approved drug
Made from
synthetic Chemically synthesised cyclohexapeptide; no biological source material 1.
Route
subcutaneous injection twice daily (Signifor), or intramuscular gluteal injection every 28 days by a healthcare professional (Signifor LAR)
Half-life
an effective half-life of approximately 12 hours after subcutaneous dosing in healthy volunteers, on average between 10 and 13 hours 1. The long-acting intramuscular formulation is dosed every 28 days and reaches pharmacokinetic steady state after three monthly doses; its duration is set by the depot rather than by the molecule 3
Onset
peak plasma concentration 0.25 to 0.5 hours after a subcutaneous dose 1. Increases in fasting glucose and HbA1c appear soon after starting and are sustained; biochemical control of acromegaly was achieved by month 3 in about 30% of drug-naive patients 13
Molecular weight
1313.41 g/mol for pasireotide diaspartate; molecular formula C58H66N10O9 · 2 C4H7NO4 1
Sequence
A cyclohexapeptide with pharmacological properties mimicking those of natural somatostatin; supplied as the diaspartate salt in the subcutaneous form

Prescription-only medicine. The twice-daily subcutaneous form was approved by the FDA on 14 December 2012 under NDA 200677 for Cushing's disease where pituitary surgery is not an option or has not been curative; the monthly intramuscular long-acting form, Signifor LAR, was approved on 15 December 2014 under NDA 203255 for acromegaly and later for Cushing's disease 1378. The EU marketing authorisation was issued on 24 April 2012 and covers both conditions, with the acromegaly indication limited to patients inadequately controlled by other somatostatin analogues; it holds EU orphan designation 2.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Pasireotide is a somatostatin analogue, but it is not simply a longer-lasting octreotide. There are five somatostatin receptor subtypes. Octreotide and lanreotide are essentially SSTR2-selective, which is what makes them effective in acromegaly, where somatotroph adenomas express SSTR2 densely. Pasireotide binds four of the five subtypes with meaningful affinity, and its highest affinity is at SSTR5 rather than SSTR2 1.

The label's own binding table makes the shape of the difference clear. Expressed as IC50 in nmol/L, pasireotide binds SSTR1 at 9.3, SSTR2 at 1.0, SSTR3 at 1.5, SSTR4 at more than 100 and SSTR5 at 0.16; native somatostatin binds the same receptors at 0.93, 0.15, 0.56, 1.5 and 0.29 1. Two things follow. Pasireotide is roughly six-fold weaker than somatostatin at SSTR2 — it is not a better SSTR2 agonist than the drugs it supplements — but it is about six times more potent at SSTR5, and roughly forty times more potent at SSTR5 than at SSTR2 within its own profile. Breadth here means a genuinely different receptor emphasis, not simply more of the same.

That emphasis is what opens Cushing's disease. Corticotroph tumour cells in Cushing's disease frequently over-express SSTR5 while expressing the other subtypes weakly or not at all, which is precisely why SSTR2-selective analogues have historically been useless in this condition. Pasireotide binds and activates the receptors that are actually there, inhibiting ACTH secretion and so reducing cortisol 1. In acromegaly the rationale is different: pasireotide is used where octreotide and lanreotide have already failed, on the reasoning that a tumour resistant to SSTR2 agonism may still respond through other subtypes.

The same receptor breadth produces the drug's defining adverse effect, and it is worth being explicit that this is mechanism rather than misfortune. SSTR5 is expressed on pancreatic beta cells and in the gut. In a randomised, double-blind mechanism study in healthy volunteers, hyperglycaemia on pasireotide was related to significant decreases in insulin secretion and in the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide 1. The drug suppresses insulin and the incretins that potentiate it, with proportionally less effect on glucagon — a combination that raises glucose in almost everyone, not just in those predisposed. Hyperglycaemia is a predictable consequence of choosing this receptor profile.

Pasireotide is metabolically stable, circulating largely unchanged, eliminated mainly by hepatic and biliary clearance with a small renal contribution — in a human mass-balance study about 48% of radioactivity was recovered in faeces and 8% in urine 1. It is not metabolised by cytochrome P450 enzymes, though as with any somatostatin analogue, suppressing growth hormone secretion may itself decrease the metabolic clearance of drugs that are CYP450 substrates 1.

What the research shows

The evidence is from randomised phase 3 trials in two rare diseases, with biochemical endpoints — urinary free cortisol in Cushing's disease, growth hormone and IGF-1 in acromegaly — rather than clinical outcomes. Where it is most convincing is in patients failing other somatostatin analogues, because there the comparator was continued failure and the difference was unambiguous. Response rates are nonetheless modest in absolute terms, and the hyperglycaemia is common enough to change the calculation for many patients.

Research in humans

In acromegaly patients inadequately controlled on octreotide or lanreotide at maximal or near-maximal doses, the PAOLA trial randomised 198 patients to pasireotide LAR 40 mg, pasireotide LAR 60 mg or continued pre-trial therapy. At 6 months, growth hormone below 2.5 mcg/L with normalised IGF-1 was achieved by 15.4% and 20.0% on the two pasireotide doses against 0% on continued therapy; IGF-1 normalised in 24.6% and 26.2% against 0% 34. In drug-naive acromegaly, a double-blind trial randomised 358 patients to pasireotide LAR or an active somatostatin analogue comparator; biochemical control at 12 months was 31.3% against 19.2% (p<0.01), and 98% of pasireotide patients had a reduction or no change in tumour volume, with a median reduction of 39.8% 35. In Cushing's disease, a 12-month phase 3 trial of the twice-daily subcutaneous form supported the original approval 6.

Animal and lab research

In embryo-fetal development studies in rabbits, findings indicating developmental delay were observed at subcutaneous doses producing less than human exposure at the highest recommended dose, without maternal toxicity 1. The label reports no carcinogenicity signal that changes prescribing, and the safety profile that matters clinically was defined in the human trials rather than in animals.

Caveats. All endpoints are biochemical surrogates. Absolute response rates are low: in patients already failing another somatostatin analogue, four out of five did not reach the combined biochemical target 3. The comparator arm in the drug-naive acromegaly trial was not given the maximum dose approved in the US, because the trial was multinational and that dose is not approved everywhere 3 — which softens the superiority claim. The trials were manufacturer-sponsored. Both conditions are rare, so the total evidence base is small, and long-term follow-up on the metabolic consequences of years of induced hyperglycaemia is limited. Whether biochemical control translates into the outcomes patients care about — cardiovascular risk, mortality, quality of life — is largely inferred from the natural history of the untreated diseases rather than demonstrated in these trials.

What it is used for

  • Cushing's disease in adults for whom pituitary surgery is not an option or has not been curative — the indication for both the twice-daily subcutaneous form and the monthly long-acting form 13
  • Acromegaly in patients with an inadequate response to surgery or for whom surgery is not an option; the EU authorisation adds the requirement that the condition is also not adequately controlled by other somatostatin analogues 23
  • In practice it occupies the position of the analogue used when octreotide and lanreotide have failed. Corticotroph adenomas in Cushing's disease over-express SSTR5 and are typically unresponsive to SSTR2-selective analogues 1, which is why pasireotide has a Cushing's indication that octreotide and lanreotide do not

Dosing

Dose
Subcutaneous (Signifor, Cushing's disease): an initial 0.6 mg or 0.9 mg twice daily, with a recommended range of 0.3 to 0.9 mg twice daily. Intramuscular long-acting (Signifor LAR): 40 mg every 28 days for acromegaly, increasing to a maximum of 60 mg; 10 mg every 28 days for Cushing's disease, increasing to a maximum of 40 mg.
Frequency
twice daily for the subcutaneous form; once every 4 weeks for the long-acting intramuscular form
Route
subcutaneous self-injection (Signifor), or intramuscular injection into the right or left gluteus by a healthcare professional, never intravenously (Signifor LAR)
Duration
Long-term, for as long as the condition requires control and the treatment is tolerated.
  • These are figures from the FDA-approved product information 13. They describe treatment of two rare pituitary conditions under specialist supervision and are reference material, not advice.
  • Baseline testing is required before the first dose and is not optional: fasting plasma glucose, HbA1c, liver tests, an ECG, gallbladder ultrasound where indicated, and serum potassium and magnesium 13. Glucose control in poorly controlled diabetes is optimised before starting 3.
  • Titration is on response and tolerability. In acromegaly, the LAR dose may rise to 60 mg if growth hormone and IGF-1 have not normalised after 3 months at 40 mg, and may be reduced in 20 mg decrements for adverse reactions or for IGF-1 below the lower limit of normal 3. In Cushing's disease, the LAR dose may rise after 4 months at 10 mg if urinary free cortisol has not normalised 3.
  • Over-treatment is a real risk in Cushing's disease, because the drug lowers cortisol towards normal and can overshoot. Hypocortisolism is managed by reducing or interrupting the dose, and sometimes by adding low-dose short-term glucocorticoid 1.
  • Hepatic impairment changes the dose: for Child-Pugh B the subcutaneous initial dose is 0.3 mg twice daily with a 0.6 mg twice daily maximum, and the LAR initial doses fall to 20 mg (acromegaly) and 10 mg (Cushing's) with maxima of 40 mg and 20 mg. Use is avoided altogether in Child-Pugh C 13.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Signifor (subcutaneous) — Cushing's disease

approved product information

Source: SIGNIFOR (pasireotide) injection FDA prescribing information

Before the first dosemeasure fasting plasma glucose, HbA1c, liver tests, ECG, serum potassium and magnesium
Initial0.6 mg or 0.9 mg by subcutaneous injection twice a day
Titration0.3 mg to 0.9 mg twice a day, adjusted on 24-hour urinary free cortisol, signs and symptoms, and tolerability
Moderate hepatic impairment (Child-Pugh B)initial 0.3 mg twice a day, maximum 0.6 mg twice a day

Use is avoided in Child-Pugh C. Intensive glucose monitoring is recommended from the start, because hyperglycaemia appears with initiation rather than later. Dose reduction or interruption, sometimes with a short course of low-dose glucocorticoid, is the response to biochemical or clinical hypocortisolism.

Signifor LAR (intramuscular) — acromegaly

approved product information

Source: SIGNIFOR LAR (pasireotide) for injectable suspension FDA prescribing information

Initial40 mg by intramuscular gluteal injection once every 4 weeks (every 28 days)
After 3 monthsmay increase to a maximum of 60 mg every 4 weeks if growth hormone and age- and sex-adjusted IGF-1 have not normalised and the dose is tolerated
For adverse reactions or over-responsedecrease temporarily or permanently in 20 mg decrements
Moderate hepatic impairment (Child-Pugh B)initial 20 mg every 4 weeks, maximum 40 mg every 4 weeks

Administered by a healthcare professional only, into the gluteus, immediately after reconstitution, and never intravenously. Pharmacokinetic steady state is reached after three monthly doses, which is why the first dose adjustment is not considered before 3 months.

Signifor LAR (intramuscular) — Cushing's disease

approved product information

Source: SIGNIFOR LAR (pasireotide) for injectable suspension FDA prescribing information

Initial10 mg by intramuscular gluteal injection once every 4 weeks (every 28 days)
After 4 monthsmay increase, up to a maximum of 40 mg every 4 weeks, if 24-hour urinary free cortisol has not normalised and the dose is tolerated
For adverse reactions or over-responsereduce to the previous tolerated dose, interrupt, or discontinue; at 10 mg the options are interruption or discontinuation
Moderate hepatic impairment (Child-Pugh B)initial 10 mg every 4 weeks, maximum 20 mg every 4 weeks

The Cushing's starting dose is a quarter of the acromegaly starting dose and titrates more slowly, on a 4-month rather than 3-month step. The reason is that the therapeutic target is a normal cortisol rather than a suppressed one, and overshooting produces adrenal insufficiency.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
Signifor subcutaneous: 0.3 mg/ml, 0.6 mg/ml and 0.9 mg/ml sterile solution in single-dose 1 ml glass ampoules, Signifor LAR: single-use kits of 10, 20, 30, 40 and 60 mg powder with a 2 ml prefilled diluent syringe, vial adapter and safety needle
Solvent
None for the subcutaneous ampoules. For Signifor LAR, the diluent supplied in the kit's prefilled syringe; 2 ml gives final concentrations of 5, 10, 15, 20 or 30 mg/ml depending on the kit strength.
Storage
Signifor LAR is stored at 2-8 °C and must not be frozen. The kit is left at room temperature for at least 30 minutes before reconstitution, and no longer than 24 hours; once the suspension is prepared it must be administered immediately.

Worked example

Neither presentation involves a syringe calculation. The subcutaneous ampoules are ready-made solutions containing the exact dose in 1 ml, with a deliberate 0.1 ml overfill so that a full 1 ml can be withdrawn accurately. Signifor LAR is reconstituted with the diluent syringe from its own kit and the entire contents are injected intramuscularly immediately.

The LAR label singles out two steps as critical, because getting them wrong means the dose is not delivered: the kit must reach room temperature before reconstitution, and after adding the diluent the vial must be shaken moderately in a horizontal direction for at least 30 seconds until the suspension is uniform. This is a professionally administered depot, not a patient-reconstituted vial, and manual reconstitution instructions written for research peptides do not apply.

Safety

Side effects

  • Hyperglycaemia, which is the defining adverse effect of this drug and follows directly from its receptor profile. In the phase 3 Cushing's disease trial of the subcutaneous form, hyperglycaemia-related terms were reported in 40% of patients, diabetes mellitus in 18%, raised HbA1c in 11% and type 2 diabetes mellitus in 9%. Mean fasting glucose rose from 98.6 to 125.1 mg/dL at month 6 in the 0.6 mg group and from 97.0 to 128.0 mg/dL in the 0.9 mg group, with HbA1c rising from 5.8% to 7.2% and 7.3% respectively 1
  • The same pattern in acromegaly, where an active comparator makes the size of the effect visible. In drug-naive patients on pasireotide LAR against another somatostatin analogue: hyperglycaemia 29% versus 8%, diabetes mellitus 26% versus 4%, raised blood glucose 8% versus 2% 3. In patients inadequately controlled on other analogues: hyperglycaemia 33% and 30% at the two doses against 14% on continued therapy, diabetes mellitus 21% and 31% against 9% 3
  • After stopping the subcutaneous drug, mean fasting glucose and HbA1c fell at one-month follow-up but remained above baseline; long-term follow-up data are not available 1
  • Ketoacidosis, sometimes severe, is warned about on the long-acting label; if suspected, the drug is stopped and the patient evaluated and treated promptly 3
  • Hypocortisolism — the drug can lower cortisol below normal in Cushing's disease, producing biochemical or clinical adrenal insufficiency, usually manageable by reducing or interrupting the dose and sometimes adding low-dose short-term glucocorticoid 1
  • Diarrhoea (39% in drug-naive acromegaly), nausea, abdominal pain, abdominal distension and vomiting — the gastrointestinal effects common to all somatostatin analogues 13
  • Cholelithiasis, in 26% of drug-naive acromegaly patients, and complications of it including cholecystitis and cholangitis, which have sometimes required cholecystectomy 13
  • Steatorrhoea, stool discolouration, loose stools, abdominal bloating and weight loss; new or worsening symptoms should prompt evaluation for pancreatic exocrine insufficiency 1
  • Bradycardia and QT prolongation. In healthy subjects the maximum mean placebo-subtracted QTcI change was 12.7 ms at 0.6 mg twice daily and 16.6 ms at a supratherapeutic dose, with heart rate falling by a mean of 10.9 and 15.2 bpm 1. Sinus bradycardia occurred in 10% of drug-naive acromegaly patients 3
  • Transient elevations in aminotransferases, returning to baseline by month 4 in the phase 3 trial. Across the development programme four people had concurrent ALT above 3× ULN with bilirubin above 2× ULN — one patient with Cushing's disease, who became jaundiced, and three healthy volunteers — in every case within the first 10 days and resolving on discontinuation 1
  • Injection site reactions in 17% of patients on the subcutaneous form: local pain, erythema, haematoma, haemorrhage and pruritus, resolving without intervention 1
  • Asymptomatic and reversible elevations in lipase and amylase; pancreatitis is a potential class effect through the association between gallstones and acute pancreatitis 1
  • Hypothyroidism and other pituitary hormone deficiencies, which are monitored for periodically and treated if clinically indicated 13
  • Alopecia (18-19% in the drug-naive acromegaly trial, at a rate similar to the comparator), fatigue, headache, dizziness, anaemia and raised creatine phosphokinase 3

Do not use if

  • The label lists no contraindications for either the subcutaneous or the long-acting form 13 — which is not the same as saying there is no reason to avoid it, and the warnings below carry the weight that a contraindications section usually would
  • Avoid in severe hepatic impairment (Child-Pugh C); reduce the dose in moderate impairment (Child-Pugh B) 13
  • Use with caution in patients at significant risk of QT prolongation — congenital long QT, cardiac disease, bradycardia, uncorrected hypokalaemia or hypomagnesaemia — with an ECG and electrolytes checked before dosing and during treatment 1
  • Poorly controlled diabetes should be optimised before starting, and glucose monitored intensively afterwards, because hyperglycaemia is expected rather than unusual 13
  • Pregnancy: the limited human data are insufficient to inform risk, and developmental delay was seen in rabbits at exposures below the human dose 1. Premenopausal women should be advised that treating Cushing's disease or acromegaly may restore fertility and lead to an unintended pregnancy 1
  • Safety and effectiveness in children under 18 have not been established 1

Interactions

Drugs that prolong the QT interval may have additive effects with pasireotide, and caution is required when they are combined 1. Pasireotide may decrease the relative bioavailability of ciclosporin, so ciclosporin doses may need adjusting to maintain therapeutic levels 1. As with somatostatin analogues generally, co-administration may raise blood levels of bromocriptine, and a bromocriptine dose reduction may be needed 1 — relevant because both drugs are used in pituitary disease and may be prescribed together. Suppression of growth hormone secretion by any somatostatin analogue may decrease the metabolic clearance of drugs metabolised by cytochrome P450 enzymes 1. Pasireotide itself is metabolically stable and is not a CYP450 substrate; it is likely a P-glycoprotein substrate, but P-gp inhibition with verapamil did not affect its availability in healthy volunteers 1. The most consequential interaction in practice is with antidiabetic therapy: initiation, dose adjustment or intensification of glucose-lowering treatment is frequently required, and should be anticipated rather than reacted to 13.

Sources