Signifor Injection Solution 0.6 Mg/Ml

Description

Signifor Injection Solution 0.6 mg/mL is a parenteral formulation of pasireotide, a multireceptor-targeted somatostatin analogue indicated primarily for Cushing’s disease and acromegaly under specialist supervision.

Product Identity and Regulatory Status

Signifor (international non‑proprietary name: pasireotide) is a synthetic cyclohexapeptide somatostatin analogue developed originally by Novartis and now marketed in many regions by Recordati Rare Diseases. It is authorised in the European Union and other jurisdictions as a prescription‑only medicinal product for subcutaneous administration, including a 0.6 mg solution for injection in 1 mL ampoules.

The 0.6 mg/mL solution represents an immediate‑release formulation distinct from the long‑acting depot pasireotide pamoate used in intramuscular suspensions, and regulatory dossiers clearly differentiate these presentations in terms of composition, pharmacokinetics and clinical use.

Qualitative and Quantitative Composition

Each 1 mL ampoule of Signifor 0.6 mg solution for injection contains 0.6 mg pasireotide expressed as pasireotide diaspartate as the active substance. The solution is clear, colourless and sterile, intended for single use and supplied with a nominal 0.1 mL overfill to ensure accurate withdrawal of 1 mL.

Active Ingredient

Pasireotide is a synthetic cyclohexapeptide somatostatin analogue that exhibits high binding affinity for somatostatin receptor subtypes sst1, sst2, sst3 and particularly sst5, providing a broader receptor profile than octreotide. The injectable solution uses the diaspartate salt to enhance aqueous solubility and stability, while the pharmacologically active moiety is the pasireotide base.

Excipients

The immediate‑release 0.6 mg/mL solution contains the following excipients: mannitol, tartaric acid, sodium hydroxide and water for injections. Mannitol acts as a tonicity‑adjusting agent, tartaric acid serves as a buffering component, sodium hydroxide is used for pH adjustment, and water for injections is the solvent.

Table 1. Qualitative composition of Signifor 0.6 mg/mL solution for injection

The product contains less than 1 mmol (23 mg) sodium per dose and is therefore characterised as “essentially sodium‑free”, which is clinically relevant in patients on sodium‑restricted regimens.

Pharmaceutical Form and Presentation

Signifor 0.6 mg is presented as a solution for injection intended for subcutaneous use, supplied in Type I clear glass one‑point‑cut ampoules containing 1 mL of solution. Pack sizes typically include 6 ampoules and multipacks of 18, 30 or 60 ampoules to support chronic treatment courses.

The solution is described as clear and colourless with no visible particles, and each ampoule contains an overfill to allow accurate withdrawal of the full labelled volume, which is standard for parenteral products.

Mechanism of Action

Pasireotide is a multireceptor‑targeted somatostatin analogue with high affinity for somatostatin receptor subtypes sst1, sst2, sst3 and sst5, with the greatest potency at sst5. In vitro receptor binding comparisons show that pasireotide has markedly higher affinity for sst1, sst3 and sst5 than octreotide, while maintaining relevant activity at sst2.

In Cushing’s disease, overexpression of sst5 on pituitary corticotroph adenomas allows pasireotide to inhibit adrenocorticotropic hormone (ACTH) secretion, thereby reducing cortisol production. In acromegaly, binding to pituitary somatotroph receptors leads to suppression of growth hormone (GH) and downstream lowering of insulin‑like growth factor‑1 (IGF‑1) levels.

At a systemic level, pasireotide modulates endocrine secretions in multiple organs, including the pituitary, pancreas and gastrointestinal tract, accounting for both its therapeutic effects and typical adverse reactions such as hyperglycaemia.

Indications and Clinical Use

Regulatory product information describes the 0.3, 0.6 and 0.9 mg/mL subcutaneous solutions as indicated for adult patients with:

• Cushing’s disease in whom surgery is not an option or has failed, to achieve control of hypercortisolism.

• Acromegaly in patients inadequately controlled by surgery and/or radiotherapy who are not candidates or are poorly responsive to other somatostatin analogues, depending on jurisdiction.

Therapy must be initiated and supervised by physicians experienced in the management of pituitary disorders, with access to appropriate biochemical monitoring and imaging.

Posology and Method of Administration

The 0.6 mg/mL formulation is intended exclusively for subcutaneous injection, typically into the thigh, abdomen or upper arm, with rotation of injection sites to minimise local reactions. Dosing regimens differ by indication and guideline but commonly involve twice‑daily subcutaneous administration, titrated based on clinical response and tolerability, within the approved dose range using 0.3, 0.6 or 0.9 mg ampoules.

Product information stresses that the contents of an ampoule are for single use only and any unused solution must be discarded, in line with aseptic practice for small‑volume parenterals. Patients who self‑inject require training on aseptic technique, correct ampoule opening, dose withdrawal, and injection angle and depth.

Pharmacokinetic Profile

After subcutaneous administration of the immediate‑release solution, pasireotide is rapidly absorbed, with peak plasma concentrations generally attained within a few hours. The compound displays multi‑exponential decline and a relatively long terminal half‑life, supporting twice‑daily dosing in most indications.

Pasireotide exhibits moderate distribution beyond the vascular compartment and is bound to plasma proteins to a limited extent, with the unbound fraction increasing in severe renal impairment. Metabolism is limited, and the parent drug is the predominant circulating species; excretion occurs via both biliary/faecal and renal routes, with renal impairment altering unbound exposure and necessitating caution but not universal dose adjustment.

Pharmacodynamics and Endocrine Effects

Pharmacodynamic studies show dose‑dependent suppression of pituitary hormones, particularly ACTH and GH, along with reductions in cortisol and IGF‑1 levels correlating with clinical improvement in Cushing’s disease and acromegaly. At the pancreatic level, pasireotide inhibits insulin secretion to a greater extent than glucagon, leading to an overall diabetogenic effect characterised by impaired glucose tolerance or frank hyperglycaemia in a substantial proportion of patients.

The drug may also reduce secretion of other pituitary and gastrointestinal hormones, contributing to adverse effects such as gastrointestinal disturbances and potential gallbladder motility changes. Cardiac electrophysiology studies indicate a potential for modest QT interval prolongation, warranting caution in patients with additional risk factors.

Clinical Efficacy Overview

Randomised phase III trials in Cushing’s disease demonstrated that pasireotide produced clinically meaningful reductions in 24‑hour urinary free cortisol, with a subset of patients achieving normalisation, alongside improvements in blood pressure, weight and other manifestations of hypercortisolism. In patients with acromegaly inadequately controlled by first‑generation somatostatin analogues, pasireotide showed superior rates of biochemical control (GH and IGF‑1 normalisation) in some studies, albeit with increased hyperglycaemia.

Response to therapy is heterogeneous, and product information recommends early and regular reassessment of cortisol or IGF‑1 levels and clinical status to determine continuation or dose adjustment.

Safety Profile and Adverse Reactions

The overall safety profile of Signifor 0.6 mg/mL solution reflects its somatostatin analogue class, with additional emphasis on glucose metabolism disturbances.

Metabolic Effects

Hyperglycaemia and diabetes mellitus are among the most frequent and clinically significant adverse events, often manifesting early after treatment initiation. The mechanism involves potent inhibition of insulin secretion, with relatively lesser suppression of glucagon, leading to elevated fasting and post‑prandial glucose levels.

Clinical management requires baseline and periodic monitoring of fasting plasma glucose and HbA1c, along with proactive institution or adjustment of antidiabetic therapy where necessary. Treatment interruption or dose modification may be warranted for uncontrolled hyperglycaemia despite optimised antidiabetic regimens.

Gastrointestinal and Hepatobiliary Effects

Common gastrointestinal adverse reactions include diarrhoea, abdominal pain, nausea and vomiting, reflecting inhibition of gastrointestinal hormone secretion and motility. Gallbladder‑related events, including cholelithiasis and biliary sludge, may occur, and ultrasound monitoring is advised in long‑term therapy analogous to other somatostatin analogues.

Mild to moderate, usually reversible elevations in liver enzymes have been reported, and periodic monitoring of hepatic function is recommended, particularly in patients with pre‑existing liver disease.

Cardiac and Other Effects

Pasireotide can cause bradycardia and modest prolongation of the QT interval, necessitating caution in patients with pre‑existing cardiac disease, electrolyte disturbances or concomitant QT‑prolonging medications. Injection‑site reactions such as pain, erythema or pruritus are generally mild and transient and may be mitigated by site rotation and proper technique.

Contraindications and Special Warnings

Signifor is contraindicated in patients with known hypersensitivity to pasireotide or any excipient of the formulation. Special warnings emphasise the risks of severe hyperglycaemia, potential adrenal insufficiency on abrupt cortisol reduction, bradycardia and QT prolongation, and gallbladder disease.

Product information recommends caution and enhanced monitoring in patients with:

• Poorly controlled diabetes or risk factors for hyperglycaemia.

• History of significant cardiac disease or arrhythmias.​

• Severe renal impairment or end‑stage renal disease because of altered unbound exposure.​

• Hepatic impairment, in which exposure may be increased and dose adjustments may be necessary according to local labelling.

Patients should be advised on symptoms of hyperglycaemia, adrenal insufficiency and gallbladder complications and instructed to seek urgent medical care if severe manifestations occur.​

Drug–Drug Interactions

Due to its potential effects on cardiac conduction, concomitant use of pasireotide with medicinal products known to prolong the QT interval (e.g. certain antiarrhythmics, macrolide antibiotics, antipsychotics, some antimalarials and fluoroquinolones) requires careful benefit–risk assessment and ECG monitoring. The impact on cytochrome P450 enzymes is limited, but modulation of pituitary and gastrointestinal hormones can indirectly influence the pharmacokinetics and pharmacodynamics of other drugs, for example by altering gastric motility.

Co‑administration with antidiabetic agents is common and often necessary; dose adjustments of insulin or oral antidiabetics are frequently required to manage pasireotide‑induced hyperglycaemia. Clinicians should also consider the additive effects with other somatostatin analogues or agents affecting gallbladder motility.

Use in Specific Populations

Clinical data in paediatric populations are limited, and the product information generally does not recommend routine use in children and adolescents outside controlled clinical settings. In elderly patients, no universal dose adjustment is mandated, but increased vigilance for metabolic and cardiac adverse events is warranted due to comorbidities.

Renal impairment increases unbound pasireotide exposure, and labelling advises caution in severe renal impairment or end‑stage renal disease rather than a fixed adjustment for all patients. Hepatic impairment can also affect exposure, and prescribers are referred to local prescribing information for recommended dose modifications.

Storage, Handling and Stability

The subcutaneous solution is manufactured by a standard aseptic parenteral process with validated in‑process controls to ensure sterility, particulate clarity and content uniformity. Ampoules should be stored according to the conditions specified in the local summary of product characteristics, protected from light and not frozen; shelf‑life and in‑use stability are defined by the manufacturer and must be respected.

Once an ampoule is opened, the solution should be used immediately and any unused portion discarded, as the product does not contain antimicrobial preservatives and is intended strictly for single use.

Summary

Signifor Injection Solution 0.6 mg/mL is a sterile, clear, subcutaneous formulation of pasireotide diaspartate with mannitol, tartaric acid, sodium hydroxide and water for injections as excipients. Its broad somatostatin receptor binding profile, particularly its high affinity for sst5, underpins its role in the medical management of Cushing’s disease and acromegaly when surgery is unsuitable or inadequate, while its use requires careful, specialist‑led monitoring of glucose metabolism, cardiovascular parameters and hepatobiliary safety.

For patient‑specific decisions, dosing, and monitoring, clinicians must always consult the current local prescribing information and relevant clinical guidelines.