Signifor LAR

Signifor LAR Adverse Reactions

pasireotide

Manufacturer:

Novartis

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Adverse Reactions
Summary of the safety profile: The safety profile of pasireotide intramuscular use is consistent with the somatostatin analogue class, except for the higher degree and frequency of hyperglycaemia seen with pasireotide intramuscular use. The safety profile of pasireotide intramuscular use was largely similar between the acromegaly and Cushing's disease indications.
Acromegaly: In acromegaly, the safety assessment was made based on 491 patients who received pasireotide (419 patients received pasireotide intramuscular use and 72 received pasireotide subcutaneous use) in phase I, II and III studies. The most common adverse reactions (incidence ≥1/10) from the pooled safety data from the phase III studies C2305 and C2402 were (in decreasing order): diarrhoea (most common in study C2305), cholelithiasis, hyperglycaemia (most common in study C2402) and diabetes mellitus. Common Toxicity Criteria (CTC) Grade 3 and 4 adverse reactions were mostly related to hyperglycaemia.
Cushing's disease: In Cushing's disease, the safety assessment of the intramuscular formulation was made based on 150 patients who received pasireotide in the phase III study G2304 (median duration of exposure: 57 weeks). Patients were randomised in a 1:1 ratio to receive starting doses of either 10 mg or 30 mg pasireotide, with a possibility to up-titrate to a maximum dose of 40 mg every 28 days. The most common adverse reactions (incidence ≥1/10) in the phase III study G2304 were hyperglycaemia, diarrhoea, cholelithiasis and diabetes mellitus. The frequency and severity of adverse reactions tended to be higher with the higher starting dose of 30 mg, but this was not consistent for all adverse reactions.
Tabulated list of adverse reactions: The adverse reactions in Table 5 include events reported in the pivotal studies with the intramuscular formulation in patients with acromegaly and with Cushing's disease. Adverse reactions are listed according to MedDRA primary system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies were defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). (See Table 5.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Glucose metabolism disorders: Acromegaly: In acromegaly patients elevated fasting glucose level was the most frequently reported grade 3/4 laboratory abnormality in the two phase III studies. In study C2305, grade 3 elevated fasting glucose levels were reported in 9.7% and 0.6% and grade 4 in 0.6% and 0% of acromegaly patients treated with pasireotide intramuscular use and octreotide intramuscular use, respectively. In study C2402, grade 3 elevated fasting glucose levels were reported in 14.3% and 17.7% of acromegaly patients treated with pasireotide intramuscular use 40 mg and 60 mg respectively, and in no patients in the active control group. Two cases of hyperglycaemia-related emergencies (diabetic ketoacidosis and diabetic hyperglycaemic coma) were reported following a dose increase of pasireotide to 60 mg in medical treatment naïve patients; one in a patient with untreated hyperglycaemia and HbA1c >8% prior to initiation of pasireotide and the other in a patient with untreated hyperglycaemia and a fasting plasma glucose of 359 mg/dl, respectively. In both studies, mean FPG and HbA1c levels peaked within the first three months of treatment with pasireotide intramuscular use. In medically naïve patients (study C2305), the mean absolute increase in FPG and HbA1c was similar at most of the time points for all patients treated with pasireotide intramuscular use irrespective of baseline values.
The degree and frequency of hyperglycaemia observed in the two pivotal studies in acromegaly patients were higher with Signifor LAR intramuscular use than with active control (octreotide intramuscular use or lanreotide deep subcutaneous injection). In a pooled analysis of the two pivotal studies, the overall incidence of hyperglycaemia-related adverse reactions was 58.6% (all grades) and 9.9% (CTC Grade 3 and 4) for Signifor LAR intramuscular use versus 18.0% (all grades) and 1.1% (CTC Grade 3 and 4) for the active control. In the pivotal study with patients inadequately controlled on another somatostatin analogue, the proportion of patients not previously treated with anti-diabetic agents who required commencement of anti-diabetic therapy during the study was 17.5% and 16.1% in the Signifor LAR 40 mg and 60 mg arms compared to 1.5% in the active control arm. In the pivotal study with patients who did not receive prior medical treatment, the proportion of patients who required commencement of anti-diabetic therapy during the study was 36% in the Signifor LAR arm compared to 4.4% in the active control arm.
Cushing's disease: In Cushing's disease patients, elevated FPG levels was the most frequently reported CTC Grade 3 laboratory abnormality (14.7% of patients) in the phase III study G2304; with no cases of Grade 4 reported. Mean HbA1c increases were less pronounced in patients with normal glycaemia at study entry in comparison to pre-diabetic patients or diabetic patients. Mean FPG levels commonly increased within the first month of treatment with decreases and stabilisation observed in subsequent months. FPG and HbA1c increases were dose-dependent, and values generally decreased following pasireotide intramuscular use discontinuation but remained above baseline values. The overall incidence of hyperglycaemia-related adverse reactions was 75.3% (all grades) and 22.7% (CTC Grade 3). Adverse reactions of hyperglycaemia and diabetes mellitus led to study discontinuation in 3 (2.0%) and 4 patients (2.7%), respectively.
The elevations of fasting plasma glucose and HbA1c observed with pasireotide intramuscular use treatment are reversible after discontinuation.
Monitoring of blood glucose levels in patients treated with Signifor LAR is recommended (see Precautions).
Gastrointestinal disorders: Gastrointestinal disorders were frequently reported with Signifor LAR. These reactions were usually of low grade, required no intervention and improved with continued treatment. In acromegaly patients, gastrointestinal disorders were less frequent in inadequately controlled patients compared to medically naïve patients.
Injection site reactions: In the phase III studies, injection site related reactions (e.g. injection site pain, injection site discomfort) were mostly grade 1 or 2 in severity. The incidence of such events was highest in the first 3 months of treatment. In the acromegaly studies, the events were comparable between pasireotide intramuscular use and octreotide intramuscular use treated patients, and were less frequent in inadequately controlled patients compared to medically naïve patients.
QT prolongation: In the acromegaly study C2305, the proportion of patients with newly occurring notable QT/QTc intervals was comparable between pasireotide intramuscular use and octreotide intramuscular use groups up to crossover, with few notable outlying values. QTcF >480 ms was reported for 3 versus 2 patients in the pasireotide intramuscular use and octreotide intramuscular use groups, respectively, and QTcF >60 ms prolonged from baseline was reported for 2 versus 1 patients in the respective groups. In study C2402, the only notable outlier was a QTcF value >480 ms in 1 patient in the pasireotide intramuscular use 40 mg group. In the Cushing's disease study G2304, a QTcF value >480 ms was reported for 2 patients. No QTcF values >500 ms were observed in any of the pivotal studies.
Liver enzymes: Transient elevations in liver enzymes have been reported with the use of somatostatin analogues and were also observed in healthy subjects and patients receiving pasireotide in clinical studies. The elevations were mostly asymptomatic, of low grade and reversible with continued treatment. A few cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have been observed with the subcutaneous formulation, however not in patients treated with pasireotide intramuscular use. All observed cases of concurrent elevations were identified within ten days of initiation of treatment. The patients recovered without clinical sequelae and liver function test results returned to baseline values after discontinuation of treatment.
Monitoring of liver enzymes is recommended before and during treatment with Signifor LAR (see Precautions), as clinically appropriate.
Pancreatic enzymes: Asymptomatic elevations in lipase and amylase were observed in patients receiving pasireotide in clinical studies. The elevations were mostly low grade and reversible while continuing treatment. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogues due to the association between cholelithiasis and acute pancreatitis.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $768 a year.
Sign up for free
Already a member? Sign in