PALSONIFY Film-coated tablet Ref.[116552] Active ingredients: Paltusotine

Tumour expansion

As growth hormone (GH)-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.

Women of childbearing potential

The therapeutic benefits of a reduction in GH levels and normalisation of IGF-1 concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with paltusotine (see section 4.6).

Cardiovascular abnormalities

Cardiac conduction abnormalities and other ECG changes such as PR interval prolongation and bradycardia have occurred during treatment with paltusotine in clinical studies (see section 4.8). These ECG changes may occur in patients with acromegaly. Dose adjustments of concomitantly used medicinal products that have bradycardia effects (e.g. beta blockers) may be necessary (see section 4.5).

Gallbladder-related events

Palsonify may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder stones or sludge. Cholelithiasis and its complications have been reported with the use of paltusotine (see section 4.8). If complications of cholelithiasis are suspected, evaluation and appropriate treatment should be initiated, and benefit-risk should be considered in determining whether or not to continue treatment with paltusotine.

Glucose metabolism

Because of its effect on GH, glucagon, and insulin, paltusotine may affect glucose regulation. Hyperglycaemia was reported in patients treated with Palsonify in clinical studies (see section 4.8). Blood glucose levels should be monitored when Palsonify treatment is initiated or the dose is altered, and antidiabetic treatment should be adjusted accordingly (see section 4.5).

Thyroid function abnormalities

Somatostatin analogues may suppress the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Periodic assessment of thyroid function (TSH and total and/or free T4) is recommended during treatment with paltusotine (see section 4.5).

Nutrition

Somatostatin analogues may alter absorption of dietary fats in some patients.

Vitamin B12 deficiency

Decreased vitamin B12 levels have been observed in patients treated with somatostatin analogues. Vitamin B12 levels during treatment with Palsonify should be monitored if clinically indicated.

Agents that may decrease paltusotine plasma concentration

Strong inducers of multiple enzymes and transporters (CYP3A4/5, UGT1A1, and P-gp)

A clinical study in healthy subjects showed following a 60 mg paltusotine administration, carbamazepine, a strong inducer of CYP3A4/5, UGT1A1, and P-gp, decreased paltusotine C_max and AUC by approximately 40% and 70%, respectively. Co-administration of paltusotine with strong inducers may thus decrease the therapeutic response.

In case of co-administration with strong inducers (e.g. carbamazepine), based on IGF-1 levels and patient's safety, paltusotine dose should be increased up to three-fold the therapeutic dose without exceeding 120 mg daily (see section 4.2).

Moderate or weak inducers of CYP3A4/P-gp

Based on the observed 70% decrease in paltusotine exposure following strong inducer (carbamazepine), a smaller decrease in exposure is expected following moderate or weak inducer. Co-administration of paltusotine with a moderate (e.g. efavirenz) or weak (e.g. prednisone) CYP3A4/P-gp inducer may thus decrease therapeutic response and dose adjustment may be necessary according to the clinical response.

In case of co-administration with moderate (e.g. efavirenz) or weak (e.g. prednisone) CYP3A4/P-gp inducers, based on IGF-1 levels and patient's safety, paltusotine dose may be increased without exceeding 120 mg daily (see section 4.2).

Proton pump inhibitors

A clinical study in healthy subjects showed PPIs caused a dose-dependent decreases in paltusotine AUC by approximately 20% and 40% following 20 mg and 60 mg paltusotine dose, respectively.

Co-administration of paltusotine with PPIs demonstrated a dose-dependent decrease in paltusotine exposure that may thus decrease therapeutic response and dose adjustment may be necessary according to the clinical response.

In case of co-administration with PPIs (e.g. lansoprazole, omeprazole), dose of paltusotine may be increased to two-fold the therapeutic dose based on IGF-1 levels and patient's safety (see section 4.2).

Cyclosporine

A clinical study conducted in healthy subjects showed, following 200 mg cyclosporine administration, paltusotine exposure was increased by ≤ two-fold. No paltusotine dose adjustment is necessary.

Effects of paltusotine on the pharmacokinetics of other medicinal products

Cyclosporine

A clinical study in healthy subjects, 40 mg paltusotine caused approximately 50% and 35% decreases in cyclosporine C_max and AUC in whole blood, respectively. Co-administration of paltusotine with cyclosporine resulted in a decrease in cyclosporine bioavailability.

Adjustment of cyclosporine dose to maintain therapeutic levels may be necessary. Recommended therapeutic medicinal product monitoring for cyclosporine should be followed.

CYP3A4 substrates

A clinical study in healthy subjects, 60 mg paltusotine caused approximately 30% increases in AUC of midazolam, a CYP3A4 substrate. Dose adjustments for CYP3A4 substrates without a narrow therapeutic index are not necessary. Caution and appropriate monitoring are recommended if paltusotine is co-administered with a CYP3A4 substrate with a narrow therapeutic index (e.g. tacrolimus).

CYP2D6 substrates

In vitro, paltusotine is an inhibitor of CYP2D6 (see section 5.2). Caution is advised if paltusotine is co-administered with a CYP2D6 substrate (e.g. carvedilol, nebivolol, metoprolol, fluoxetine, or dextromethorphan). No clinical drug-drug interaction study was performed. Dose adjustments for CYP2D6 substrates are not necessary.

P-gp substrates

In vitro, paltusotine is an inhibitor of P-gp (see section 5.2). Caution is advised if paltusotine is co-administered with a P-gp substrate with a narrow therapeutic index (e.g. digoxin). No clinical drug-drug interaction study was performed. Dose adjustments for P-gp substrates are not necessary.

Metformin

A clinical study in healthy volunteers, showed concomitant administration of metformin and paltusotine resulted in a decrease in metformin exposure by 22%, C_max by 39%. The clinical result is considered relevant as this result is not expected based on in vitro finding of MATE inhibition by paltusotine. Nevertheless, the change in metformin exposure is not considered clinically significant. Therefore, no dose adjustment is necessary.

Pharmacodynamic interactions

Antidiabetic medicinal products

Dose adjustments of insulin and antidiabetic medicinal products may be required when paltusotine is administered concomitantly (see section 4.4).

Cardiovascular medicinal products

Dose adjustment of medicinal products that have bradycardic effects, such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary (see section 4.4).

Thyroid hormones replacement therapy

Somatostatin analogues may affect thyroid function (see sections 4.4). Therefore, monitoring of thyroid function and clinical monitoring is recommended during concomitant treatment thyroid hormone replacement therapy as this may lead to thyroid imbalance.

Pregnancy

There are limited data from the use of paltusotine in pregnant women. Animal studies do not indicate direct or indirect harmful effects at human exposure with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Palsonify during pregnancy.

Breast-feeding

It is unknown whether paltusotine/metabolites are excreted in human milk. Available toxicological data in animals have shown excretion of paltusotine/metabolites in milk (see section 5.3). A risk to the suckling newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Palsonify.

Fertility

No human data on the effect of paltusotine on fertility are available. Although no effects on mating or fertility were identified in animal studies, changes in reproductive parameters were reported in female rats (see section 5.3).

Palsonify has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Gastrointestinal symptoms of diarrhoea (18%), abdominal pain (7%), nausea (5%) and abdominal discomfort (3%) were the most frequently reported adverse reactions with paltusotine.

Tabulated list of adverse reactions

The safety of paltusotine was evaluated in 169 adults with acromegaly in two randomised, double-blind, placebo-controlled studies.

A total of 233 patients were exposed to paltusotine in all phase 2 and 3 and open label extension (OLE) acromegaly studies. The median duration of treatment with paltusotine in patients with acromegaly was 65.4 weeks (range: 0.7 to 244.3 weeks).

Adverse reactions are listed by MedDRA system organ class (SOC) and frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions:

^a Sinus bradycardia includes preferred terms: sinus bradycardia and bradycardia.

Description of selected adverse reactions

Bradycardia

Events of bradycardia occurred in 6% of patients treated with paltusotine, were asymptomatic and did not lead to the discontinuation of the medicinal product. The events occurred in patients with and without a history of bradycardia, occurred in the first three months of treatment and there was no clear dose association. The mean reduction in heart rate was 6 beats per minute (bpm) (see section 4.4).

Gallbladder-related adverse reactions

In randomised studies, cholelithiasis occurred between 6 and 9 months after the start of paltusotine. In all patients exposed to paltusotine in the clinical development program, cholelithiasis occurred in 4.7% and bile duct stone in 0.4%. In patients who had not received previous treatment with somatostatin receptor ligand therapies, cholelithiasis was reported in 8.3% (2/24) of patients. No patients discontinued paltusotine due to cholelithiasis (see section 4.4).

Gastrointestinal disorders

Most gastrointestinal adverse reactions occurred within the first two months of paltusotine initiation, all were non serious and had a median duration ranging between 4 to 12 days. The majority of the adverse reaction were mild, none were severe and improved with continued treatment. There were no discontinuations due to gastrointestinal adverse reactions.

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 via the national reporting system listed in Appendix V.

Not applicable.