RETSEVMO Hard capsule Ref.[28022] Active ingredients: Selpercatinib

Interstitial Lung Disease (ILD) / Pneumonitis

Severe, life-threatening, or fatal cases of ILD/pneumonitis have been reported in patients treated with selpercatinib (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Selpercatinib should be withheld, and patients should be promptly investigated for ILD if they present with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnoea, cough, and fever), and treated as medically appropriate. Based on the severity of ILD/pneumonitis, the dose of selpercatinib should be interrupted, reduced, or permanently discontinued (see section 4.2).

Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST)

Grade ≥3 increased ALT and Grade ≥3 increased AST were reported in patients receiving selpercatinib (see section 4.8). ALT and AST should be monitored prior to the start of selpercatinib therapy, every 2 weeks during the first 3 months of treatment, monthly for the next 3 months of treatment, and otherwise as clinically indicated. Based on the level of ALT or AST elevations, selpercatinib may require dose modification (see section 4.2).

Hypertension

Hypertension was reported in patients receiving selpercatinib (see section 4.8). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. Based on the level of increased blood pressure, selpercatinib may require dose modification (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy.

QT interval prolongation

QT interval prolongation was reported in patients receiving selpercatinib (see section 5.1). Selpercatinib should be used with caution in patients with such conditions as congenital long QT syndrome or acquired long QT syndrome or other clinical conditions that predispose to arrhythmias. Patients should have a QTcF interval of ≤470 ms and serum electrolytes within normal range before starting selpercatinib treatment. Electrocardiograms and serum electrolytes should be monitored in all patients after 1 week of selpercatinib treatment, at least monthly for the first 6 months and otherwise, as clinically indicated, adjusting frequency based upon risk factors including diarrhoea, vomiting, and/or nausea. Hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiating selpercatinib and during treatment. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval. Selpercatinib may require dose interruption or modification (see section 4.2).

Hypothyroidism

Hypothyroidism has been reported in patients receiving selpercatinib (see section 4.8). Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism should be treated as per standard medical practice prior to the start of selpercatinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during selpercatinib treatment. Thyroid function should be monitored periodically throughout treatment with selpercatinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice, however patients could have an insufficient response to substitution with levothyroxine (T4) as selpercatinib may inhibit the conversion of levothyroxine to liothyronine (T3) and supplementation with liothyronine may be needed (see section 4.5).

Strong CYP3A4 inducers

Concomitant use of strong CYP3A4 inducers should be avoided due to the risk of decreased efficacy of selpercatinib (see section 4.5).

Women of childbearing potential / Contraception in females and males

Women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib (see section 4.6).

Fertility

Based on nonclinical safety findings, male and female fertility may be compromised by treatment with Retsevmo (see sections 4.6 and 5.3). Both men and women should seek advice on fertility preservation before treatment.

Hypersensitivity

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed in patients with NSCLC previously treated with anti-PD-1/PD-L1 immunotherapy (see section 4.8). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or elevated aminotransferases.

Suspend selpercatinib if hypersensitivity occurs, and begin steroid treatment. Based on the grade of hypersensitivity reactions, selpercatinib may require dose modification (see section 4.2). Steroids should be continued until patient reaches target dose and then tapered. Permanently discontinue selpercatinib for recurrent hypersensitivity.

Haemorrhages

Serious including fatal haemorrhagic events were reported in patients receiving selpercatinib (see section 4.8).

Permanently discontinue selpercatinib in patients with severe or life-threatening haemorrhage (see section 4.2).

Tumour lysis syndrome (TLS)

Cases of TLS have been observed in patients treated with selpercatinib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated as clinically indicated, and appropriate prophylaxis including hydration should be considered.

Effects of other medicinal products on the pharmacokinetics of selpercatinib

Selpercatinib metabolism is through CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of selpercatinib.

Selpercatinib is a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in vitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oral bioavailability is 73% and its exposure was increased minimally by co-administration of the P-gp inhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC_0-24 and C_max, respectively).

Agents that may increase selpercatinib plasma concentrations

Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A inhibitor, increased the C_max and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be coadministered, the dose of selpercatinib should be reduced (see section 4.2).

Agents that may decrease selpercatinib plasma concentrations

Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately 87% and 70% in selpercatinib AUC and C_max, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided.

Effects of selpercatinib on the pharmacokinetics of other medicinal products (increase in plasma concentration)

Sensitive CYP2C8 substrates

Selpercatinib increased the C_max and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188% respectively. Therefore, coadministration with sensitive CYP2C8 substrates (e.g., odiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir and montelukast), should be avoided.

Sensitive CYP3A4 substrates

Selpercatinib increased C_max and AUC of midazolam (a CYP3A4 substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g., alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, vardenafil), should be avoided.

Coadministration with medicinal products that affect gastric pH

Selpercatinib has pH-dependent solubility, with decreased solubility at higher pH. No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H₂ receptor antagonist) given 2 hours after the selpercatinib dose.

Coadministration with medicinal products that are proton pump inhibitors

Coadministration with multiple daily doses of omeprazole (a proton pump inhibitor) decreased selpercatinib AUC_0-INF and C_max when selpercatinib was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-INF and C_max when Retsevmo was administered with food.

Coadministration with medicinal products that are substrates of transporters

Selpercatinib inhibits the renal transporter multidrug and toxin extrusion protein 1 (MATE1). In vivo interactions of selpercatinib with clinically relevant substrates of MATE1, such as creatinine, may occur (see section 5.2).

Selpercatinib is an in vitro inhibitor of P-gp and BCRP. In vivo, selpercatinib increased C_max and AUC of dabigatran, a P-gp substrate, by 43% and 38%, respectively. Therefore, caution should be used when taking a sensitive P-gp substrate (e.g., fexofenadine, dabigatran etexilate, colchicine, saxagliptin), and particularly those with a narrow therapeutic index (e.g., digoxin) (see section 5.2).

Medicinal products that may be less effective when given with selpercatinib

Selpercatinib could inhibit D2 deiodinase and thereby decrease the conversion of levothyroxine (T4) to liothyronine (T3). Patients could therefore have an insufficient response to substitution with levothyroxine and supplementation with liothyronine may be needed (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential have to use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib.

Pregnancy

There are no available data from the use of selpercatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Retsevmo is not recommended during pregnancy and in women of childbearing potential not using contraception. It should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Retsevmo and for at least one week after the last dose.

Fertility

No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with Retsevmo (see section 5.3). Both men and women should seek advice on fertility preservation before treatment.

Retsevmo may have minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with Retsevmo (see section 4.8).

Summary of the safety profile

The most common serious adverse drug reactions (ADRs) are abdominal pain (2.5%), hypersensitivity (2.0%), diarrhoea (1.9%), ALT increased (1.5%) and AST increased (1.5%).

Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.0% of patients. ADRs resulting in permanent discontinuation (2 or more patients) included increased ALT (0.6%), fatigue (0.6%), increased AST (0.5%), hypersensitivity (0.3%), and thrombocytopenia (0.3%).

Tabulated list of adverse drug reactions

The ADRs reported in patients treated with selpercatinib are shown in Table 3. The ADRs are classified according to the MedDRA system organ class. Frequency groups are defined by 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), and not known (cannot be estimated from available data).

Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Median time on treatment with selpercatinib was 21.3 months.

Table 3. Adverse drug reactions in patients receiving single agent selpercatinib (LIBRETTO-001; N=796):

^* Only includes grade 3 adverse reactions. a Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient’s first cycle of treatment (typically between Days 7-21).
^b Based on laboratory assessments. Percentage is calculated based on the number of patients with baseline assessment and at least one post-baseline assessment as the denominator, which was 765 for lymphocyte count decrease, 787 for magnesium decreased and 791 for the others.
^c Hypersensitivity includes drug hypersensitivity and hypersensitivity
^d Headache includes headache, sinus headache and tension headache. e Dizziness includes dizziness, vertigo, presyncope and dizziness postural.
^f Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and Electrocardiogram QT interval abnormal.
^g Hypertension includes hypertension and blood pressure increased.
^h Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain.
ⁱ Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements and gastrointestinal hypermotility.
^j Dry mouth includes dry mouth and mucosal dryness.
^k Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash pruritic, rash papular, rash morbilliform.
^l Fatigue includes fatigue, asthenia and malaise.
^m Oedema includes oedema peripheral, face oedema, periorbital oedema, swelling face, peripheral swelling, localised oedema, eyelid oedema, eye swelling, lymphoedema, orbital oedema, eye oedema, oedema, swelling, scrotal oedema and scrotal swelling.
ⁿ Haemorrhage includes epistaxis, haematuria, contusion, haemoptysis, rectal haemorrhage, haematochezia, ecchymosis, petechiae, vaginal haemorrhage, blood urine present, gastric haemorrhage, traumatic haematoma, cerebral haemorrhage, gingival bleeding, mouth haemorrhage, purpura, blood blister, haemorrhage intracranial, spontaneous haematoma, subarachnoid haemorrhage, subdural haemorrhage, abdominal wall haematoma, anal haemorrhage, angina bullosa haemorrhagica, conjunctival haemorrhage, disseminated intravascular coagulation, diverticulum intestinal haemorrhagic, eye haemorrhage, gastrointestinal haemorrhage, haematemesis, haemorrhage, haemorrhage subcutaneous, haemorrhagic stroke, haemorrhoidal haemorrhage, hepatic haematoma, hepatic haemorrhage, intra-abdominal haemorrhage, laryngeal haemorrhage, lower gastrointestinal haemorrhage, melaena, occult blood positive, pelvic haematoma, periorbital haematoma, periorbital haemorrhage, pharyngeal haemorrhage, post procedural haemorrhage, postmenopausal haemorrhage, pulmonary contusion, retinal haemorrhage, retroperitoneal haematoma, scleral haemorrhage, skin haemorrhage, upper gastrointestinal haemorrhage, uterine haemorrhage and vessel puncture site haematoma.
^o Interstitial lung disease/pneumonitis includes pneumonitis, radiation pneumonitis, alveolitis, bronchiolitis, and pulmonary radiation injury.

Description of selected adverse reactions

Aminotransferase elevations (AST/ALT increased)

Based on laboratory assessment, ALT and AST elevations were reported in 55.5% and 58.9% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 11.8% and 10.6% patients respectively.

The median time to first onset was: AST increase 4.3 weeks (range: 0.7, 151.7), ALT increase 4.3 weeks (range: 0.9, 144.0).

Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2).

QT interval prolongation

In the 792 patients who had ECGs, review of data showed 7.3% of patients had >500 msec maximum post-baseline QTcF value, and 19.8% of patients had a >60 msec maximum increase from baseline in QTcF intervals. At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.1% of patients.

There were no reports of Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, or ventricular flutter related to selpercatinib. No patient discontinued treatment due to QT prolongation.

Retsevmo may require dose interruption or modification (see sections 4.2 and 4.4).

Hypertension

In the 793 patients who had blood pressure measurements, the median maximum increase from baseline systolic pressure was 31 mm Hg (range: –12, +96). Only 10.8% of patients retained their baseline grade during treatment, 42.2% had an increasing shift of 1 grade, 37.1% of 2 grades, and 9.3% of 3 grades. A treatment emergent adverse event of hypertension was reported in 43.9% patients with history of hypertension (28.2% with grade 3, 4) and 38.8% of patients without history of hypertension (13.7% with grade 3, 4).

Overall, a total of 19.6% displayed treatment-emergent Grade 3 hypertension (defined as maximum systolic blood pressure greater than 160 mm Hg). Grade 4 treatment emergent hypertension was reported in 0.1% of patients. Diastolic blood pressure results were similar, but the increases were of lesser magnitude.

One patient was permanently discontinued due to hypertension. Dose modification is recommended in patients who develop hypertension (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy (see section 4.4).

Hypersensitivity

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or increased aminotransferase.

In study LIBRETTO-001, 24.7% (197/796) of patients treated with selpercatinib had previously received anti-PD-1/PD-L1 immunotherapy. Hypersensitivity occurred in a total of 5.9% (47/796) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.9% (15/796) of patients. Of the 47 patients with hypersensitivity, 55.3% (26/47) had NSCLC and had received prior anti-PD-1/PD-L1 immunotherapy.

Grade 3 hypersensitivity occurred in 3.6% (7/197) of the patients previously treated with anti-PD-1/PD-L1 immunotherapy.

The median time to onset was 1.9 weeks (range: 0.7 to 112.1 weeks): 1.7 weeks in patients with previous anti-PD-1/PD-L1 immunotherapy and 4.4 weeks in patients who were anti-PD-1/PD-L1 immunotherapy naïve.

Retsevmo may require dose interruption or modification (see section 4.2).

Haemorrhages

Grade ≥3 haemorrhagic events occurred in 3.1% of patients treated with selpercatinib, including 4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one case each of tracheostomy site haemorrhage, and haemoptysis. The median time to onset was 24.3 weeks (range: 0.1 week to 147.6 weeks).

Selpercatinib should be discontinued permanently in patients with severe or life-threatening haemorrhage (see section 4.2).

Additional information on special populations

Paediatric patients

There were 3 patients <18 years (range: 15-17) of age in LIBRETTO-001. The safety of selpercatinib in children aged less than 18 years has not been established.

Elderly

In patients receiving selpercatinib, 24.4% were ≥65-74 years of age, 8.3% were 75-84 years of age, and 1.0% ≥85 years of age. The frequency of serious adverse events reported was higher in patients ≥65-74 years (51.5%), 75-84 years (56.1%), and ≥85 years (100.0%), than in patients <65 years (39.4%) of age.

The frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥65-74 years (7.2%), 75-84 years (18.2%), and ≥85 years (25.0%), than in patients <65 years of age (6.8%).

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.