Leaflet ODOMZO 200mg capsules

Odomzo 200 mg hard capsules

Each hard capsule contains 200 mg sonidegib (as phosphate).

Each hard capsule contains 38.6 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Opaque pink hard capsule containing white to almost white powder with granules, with “NVR” imprinted inblack ink on the cap and “SONIDEGIB 200MG” imprinted in black ink on the body.

The size of the capsule is “Size #00” (dimensions 23.3 x 8.53 mm).

Odomzo is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC)who are not amenable to curative surgery or radiation therapy.

Odomzo should only be prescribed by or under the supervision of a specialist physician experienced in themanagement of the approved indication.

The recommended dose is 200 mg sonidegib taken orally once daily.

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity develops.

Dose modifications for creatine phosphokinase (CK) elevations and muscle-related adverse reactions

Temporary dose interruption and/or dose reduction of Odomzo therapy may be required for CK elevationsand muscle-related adverse reactions.

Table 1 summarises recommendations for dose interruption and/or dose reduction of Odomzo therapy in themanagement of symptomatic CK elevations and muscle-related adverse reactions (such as myalgia,myopathy, and/or spasm).

Table 1 Recommended dose modifications and management for symptomatic CK elevations andmuscle-related adverse reactions

Severity of CK elevation Dose modifications* and managementrecommendations

* Continue treatment at the same dose andmonitor CK levels weekly until resolutionto baseline level and then monthly

Grade 1 thereafter. Monitor muscle symptoms for[CK elevation >ULN - 2.5 x ULN] changes until resolution to baseline.

* Check renal function (serum creatinine)regularly and ensure that patient isadequately hydrated.

* Interrupt treatment and monitor CK levelsweekly until resolution to baseline level.

* Monitor muscle symptoms for changesuntil resolution to baseline. Uponresolution, resume treatment at the samedose level and measure CK monthlythereafter.

Grade 2 without renal impairment * Check renal function (serum creatinine)(serum Cr ≤ ULN) regularly and ensure that the patient is[CK elevation >2.5 x ULN - 5 x ULN] adequately hydrated.

* If symptoms re-occur, interrupt treatmentuntil resolution to baseline. Re-introducesonidegib at 200 mg every other day andfollow the same monitoringrecommendations. If symptoms persistdespite alternate-day dosing, considerdiscontinuing treatment.

* Interrupt treatment and monitor CK levelsweekly until resolution to baseline.

Monitor muscle symptoms for changesuntil resolution to baseline.

Grade 3 or 4 without renal impairment * Check renal function (serum creatinine)(serum Cr ≤ ULN) regularly and ensure that patient is[Grade 3 (CK elevation >5 x ULN - 10 x ULN)] adequately hydrated.

[Grade 4 (CK elevation >10 x ULN)] * If renal function is not impaired and CKresolves to baseline, consider resumingtreatment at 200 mg every other day. CKlevels should be measured weekly for2 months after re-administration ofsonidegib and monthly thereafter.

* If renal function is impaired, interrupttreatment and ensure that the patient isadequately hydrated and evaluate othersecondary causes of renal impairment.

* Monitor CK and serum creatinine levelsweekly until resolution to baseline.

Grade 2, 3 or 4 with renal impairment Monitor muscle symptoms for changes(serum Cr > ULN) until resolution to baseline.

* If CK and serum creatinine levels return tobaseline consider resuming treatment at200 mg every other day and measure CKlevels weekly for 2 months and monthlythereafter; otherwise discontinue treatmentpermanently.

* The above recommendations for dose modifications are based on the Common Terminology Criteriafor Adverse Events (CTCAE) v4.03, developed by the National Cancer Institute (USA). The CTCAEis a standardised classification of adverse events used in assessing medicinal products for cancertherapy.

Cr: creatinine; ULN: upper limit of normal

Other dose modifications

Management of severe or intolerable adverse reactions may require temporary dose interruption (with orwithout a subsequent dose reduction) or discontinuation.

When dose interruption is required, consider resuming Odomzo at the same dose after resolution of theadverse reaction to ≤ grade 1.

If dose reduction is required, then the dose should be reduced to 200 mg every other day. If the same adversedrug reaction occurs following the switch to alternate daily dosing and does not improve, considerdiscontinuing treatment with Odomzo.

Due to the long half-life of sonidegib the full effect of a dose interruption or dose adjustment of sonidegib onseveral adverse reactions is expected to generally occur after a few weeks (see section 5.2).

In clinical studies, treatment with Odomzo was continued until disease progression or until unacceptabletoxicity. Treatment interruptions of up to 3 weeks were allowed based on individual tolerability.

Benefit of continued treatment should be regularly assessed, with the optimal duration of therapy varying foreach individual patient.

Sonidegib has not been studied in a dedicated pharmacokinetic study in patients with renal impairment.

Based on the available data, sonidegib elimination via the kidney is negligible. A populationpharmacokinetic analysis found that mild or moderate renal impairment did not have a significant effect onthe apparent clearance (CL/F) of sonidegib, suggesting that dose adjustment is not necessary in patients withrenal impairment (see section 5.2). No efficacy and safety data are available in patients with severe renalimpairment.

No dose adjustment is necessary in patients with hepatic impairment (see section 5.2).

Elderly (≥65 years)

Safety and efficacy data in patients aged 65 years and older do not suggest that a dose adjustment is requiredin these patients (see section 5.2).

The safety and efficacy of Odomzo in children and adolescents aged below 18 years with basal cellcarcinoma have not been established. No data are available.

Odomzo is for oral use. The capsules must be swallowed whole. They must not be chewed or crushed. Thecapsules must not be opened due to risk of teratogenicity (see section 5.3).

Odomzo must be taken at least two hours after a meal and at least one hour before the following meal toprevent increased risk of adverse reactions due to higher exposure of sonidegib when taken with a meal (seesection 5.2). If vomiting occurs during the course of the treatment, then no re-dosing of the patient is allowedbefore the next scheduled dose.

If a dose is missed, it should be taken as soon as this is realised, unless more than six hours have passed sinceit was scheduled to be taken; in this case, the patient should wait and take the next scheduled dose.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and breast-feeding (see sections 4.4 and 4.6).

Women of childbearing potential who do not comply with the Odomzo Pregnancy Prevention Programme(see sections 4.4 and 4.6).

Muscle-related adverse reactions

In the phase II pivotal study, muscle spasms, myalgia, myopathy and cases of CK elevations were observed.

The majority of patients treated with Odomzo 200 mg daily who had grade 2 or higher CK elevationsdeveloped muscle symptoms prior to the CK elevations. For most patients, muscle symptoms and CKelevations resolved with appropriate management.

All patients starting therapy with Odomzo must be informed of the risk of muscle-related adverse reactions,including the possibility of rhabdomyolysis. They must be instructed to report promptly any unexplainedmuscle pain, tenderness or weakness occurring during treatment with Odomzo or if symptoms persist afterdiscontinuing treatment.

CK levels should be checked prior to starting treatment and as clinically indicated thereafter, e.g. ifmuscle-related symptoms are reported. If clinically notable elevation of CK is detected, renal function shouldbe assessed (see section 4.2).

Dose modification or interruption guidelines should be followed (see section 4.2). Management ofhigh-grade CK elevation using supportive therapy, including proper hydration, should be consideredaccording to local standards of medical practice and treatment guidelines.

Patients should be closely monitored for muscle-related symptoms if Odomzo is used in combination withcertain medicinal products that may increase the potential risk of developing muscle toxicity (e.g. CYP3A4inhibitors, chloroquine, hydroxychloroquine, fibric acid derivatives, penicillamine, zidovudine, niacin and

HMG-CoA reductase inhibitors) (see section 4.5).

Patients with neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophiclateral sclerosis, spinal muscular atrophy) must be closely monitored due to an increased risk of muscletoxicity.

Embryofoetal death or severe birth defects

Odomzo may cause embryo-foetal death or severe birth defects when administered to pregnant women.

Based on the mechanism of action, in animal studies, sonidegib has been shown to be teratogenic andfoetotoxic. Women taking Odomzo must not be pregnant or become pregnant during treatment and for20 months after ending treatment.

Criteria defining a woman of childbearing potential

A woman of childbearing potential is defined in the Odomzo Pregnancy Prevention Programme as a sexuallymature female who

* has menstruated at any time during the previous 12 consecutive months,

* has not undergone a hysterectomy or a bilateral oophorectomy, or who does not have medicallyconfirmed permanent premature ovarian failure,

* does not have a XY genotype, Turner’s syndrome or uterine agenesis,

* becomes amenorrhoeic following cancer therapy, including treatment with Odomzo.

For women of childbearing potential

Odomzo is contraindicated in women of childbearing potential who do not comply with the Odomzo

Pregnancy Prevention Programme. A woman of childbearing potential must understand that:

* Odomzo exposes a teratogenic risk to the unborn child.

* She must not take Odomzo if she is pregnant or plans to become pregnant.

* She must have a negative pregnancy test, conducted by a healthcare professional within 7 days beforestarting Odomzo treatment.

* She must have a negative pregnancy test monthly during treatment, even if she has becomeamenorrhoeic.

* She must not become pregnant while taking Odomzo and for 20 months after her final dose.

* She must be able to comply with effective contraceptive measures.

* She must use 2 methods of recommended contraception (see the “Contraception” section below andsection 4.6) while she is taking Odomzo, unless she commits to not having sexual intercourse(abstinence).

* She must tell her healthcare provider if any of the following occur during treatment and during the20 months after her final dose:o she becomes pregnant or thinks for any reason that she may be pregnant,o she misses her expected menstrual period,o she stops using contraception unless she commits to not having sexual intercourse (abstinence),o she needs to change contraception.

* She must not breast-feed while taking Odomzo and for 20 months after the final dose.

Sonidegib may pass into the semen. To avoid potential foetal exposure during pregnancy, a male patientmust understand that:

* Odomzo exposes a teratogenic risk to the unborn child if he engages in unprotected sexual activitywith a pregnant woman.

* He must always use the recommended contraception (see the “Contraception” section below andsection 4.6).

* He will tell his healthcare provider if his female partner becomes pregnant while he is taking Odomzoor during the 6 months after his final dose.

For healthcare professionals

Healthcare professionals must educate patients so they understand and acknowledge all the conditions of the

Odomzo Pregnancy Prevention Programme.

Women of child-bearing potential must use two methods of recommended contraception, including onehighly effective method and a barrier method, while taking Odomzo and for 20 months after endingtreatment (see section 4.6).

Male patients, even those who have had a vasectomy, must always use a condom (with spermicide, ifavailable) when having sex with a female partner while taking Odomzo and for 6 months after endingtreatment (see sections 4.6 and 5.3).

The pregnancy status of women of child-bearing potential must be established within 7 days prior to theinitiation of Odomzo treatment and monthly during treatment by means of a test performed by a healthcareprofessional. Pregnancy tests should have a minimum sensitivity of 25 mIU/ml as per local availability. Inthe event of pregnancy, treatment must not be initiated. In case of pregnancy occurring during treatment,

Odomzo must be stopped immediately (see section 5.3). Patients who present with amenorrhoea duringtreatment with Odomzo should continue monthly pregnancy testing while on treatment.

Prescribing and dispensing restrictions for women of childbearing potential

The initial prescription and dispensing of Odomzo should occur within 7 days of a negative pregnancy test.

Prescriptions of Odomzo should be limited to 30 days of treatment, with continuation of treatment requiringa new prescription.

In order to help healthcare providers and patients avoid embryonic and foetal exposure to Odomzo, the

Marketing Authorisation Holder will provide educational materials (Odomzo Pregnancy Prevention

Programme) to reinforce the potential risks associated with use of the medicinal product.

Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months afterending treatment.

Male patients should not donate semen while taking Odomzo and for at least 6 months after endingtreatment.

Premature fusion of the epiphyses

Premature fusion of the epiphyses has been reported in paediatric patients exposed to Hedgehog(Hh) pathway inhibitors. In some cases, fusion progressed after drug discontinuation (see section 4.8).

Concomitant treatment with strong CYP inducers (e.g. rifampicin, carbamazepine or phenytoin) should beavoided, as a risk for decreased plasma concentrations and decreased efficacy of sonidegib cannot beexcluded (see also section 4.5).

Patients with advanced BCC have an increased risk of developing cuSCC. Cases of cuSCC have beenreported in advanced BCC patients treated with Odomzo. It has not been determined whether cuSCC isrelated to Odomzo treatment. Therefore, all patients should be monitored routinely while taking Odomzo,and cuSCC should be treated according to the standard of care.

Additional precautions

Patients should be instructed never to give this medicinal product to another person. Any capsules thatremain unused at the end of treatment should immediately be disposed of by the patient in accordance withlocal requirements (e.g. by returning the capsules to their pharmacist or physician).

Odomzo capsules contain lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

Sonidegib undergoes metabolism primarily by CYP3A4, and concomitant administration of strong inhibitorsor inducers of CYP3A4 can increase or decrease sonidegib concentrations significantly.

Agents that may increase sonidegib plasma concentration

In healthy subjects, co-administration of a single 800 mg dose of sonidegib with ketoconazole (200 mg twicedaily for 14 days), a strong CYP3A inhibitor, resulted in a 2.25-fold and a 1.49-fold increase in sonidegib

AUC and Cmax, respectively, compared with sonidegib alone. Longer duration of concomitant use of

CYP3A4 strong inhibitors (e.g. more than 14 days) will lead to a larger fold change in sonidegib exposurebased on simulation. If concomitant use of a strong CYP3A inhibitor is required, the sonidegib dose shouldbe reduced to 200 mg every other day. Strong CYP3A inhibitors include, but are not limited to, ritonavir,saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Patientsshould be carefully monitored for adverse events if one of these agents is used together with sonidegib.

Agents that may decrease sonidegib plasma concentration

In healthy subjects, co-administration of a single dose of 800 mg sonidegib with rifampicin (600 mg daily for14 days), a strong CYP3A inducer, resulted in 72% and 54% decreases in sonidegib AUC and Cmaxrespectively, compared with when sonidegib was given alone. Co-administration of sonidegib with strong

CYP3A inducers decreases sonidegib plasma concentration. Concomitant use of strong CYP3A inducersshould be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin,rifampicin and St John’s Wort (Hypericum perforatum). If a strong CYP3A4 inducer must be usedconcomitantly with sonidegib, consideration should be given to increasing the daily dose of sonidegib to400-800 mg. This dose of sonidegib is predicted to adjust the AUC to the range observed without inducersbased on pharmacokinetic data when the concomitant treatment with the inducer is no longer than 14 days.

Longer concomitant treatment with inducer is not recommended because sonidegib exposure will bedecreased and this may compromise efficacy. The dose of sonidegib used prior to initiation of the stronginducer should be resumed if the strong inducer is discontinued.

Results from a clinical study demonstrated a change in sonidegib exposure (32% and 38% decrease in AUCand Cmax) after co-administration of a single dose of Odomzo 200 mg with esomeprazole (a proton pumpinhibitor) at 40 mg daily for 6 days in healthy subjects. This interaction is not expected to be clinicallysignificant.

Effects of sonidegib on other medicinal products

Sonidegib is a competitive inhibitor of CYP2B6 and CYP2C9 in vitro. However, results of a drug-druginteraction study in cancer patients demonstrate that the systemic exposure of bupropion (a CYP2B6substrate) and warfarin (a CYP2C9 substrate) is not altered when co-administered with sonidegib. Sonidegibis also a breast cancer resistance protein (BCRP) inhibitor (IC50 ~1.5µM). Patients concomitantly usingsubstrates of BCRP transporters should be carefully monitored for adverse drug reactions. Substances thatare BCRP substrates with narrow therapeutic range (e.g. methotrexate, mitoxantrone, irinotecan, topotecan)should be avoided.

Agents that may increase muscle-related adverse reactions

Due to overlapping toxicities, patients taking Odomzo who are also taking medicinal products known toincrease the risk of muscle-related toxicity may be at increased risk of developing muscle-related adversereactions. Patients should be closely monitored and dose adjustments should be considered if musclesymptoms develop.

In the phase II pivotal trial, 12 (15.2%) patients treated with Odomzo 200 mg took concomitant HMG-CoAreductase inhibitors (9 took pravastatin, 3 took non-pravastatin HMG-CoA reductase inhibitors includingrosuvastatin and simvastatin). Of these patients, 7 (58.3%) had up to grade 1 muscle symptoms while 43(64.1%) patients not taking HMG-CoA reductase inhibitors experienced up to grade 3 symptoms. No patienttaking HMG-CoA reductase inhibitors experienced grade 3/4 CK elevations, as opposed to 6 (9.0%) patientsnot taking HMG-CoA reductase inhibitors.

The bioavailability of sonidegib is increased in the presence of food (see section 5.2). Odomzo must be takenat least two hours after a meal and at least one hour before the following meal.

Due to the risk of embryofoetal death or severe birth defects caused by sonidegib, women taking Odomzomust not be pregnant or become pregnant during treatment and for 20 months after ending treatment (seesection 4.4).

Odomzo is contraindicated in woman of childbearing potential who do not comply with the Odomzo

Pregnancy Prevention Programme (see section 4.3).

If the patient does become pregnant, misses a menstrual period, or suspects for any reason that she may bepregnant, she must notify her treating physician immediately.

Persistent lack of menses during treatment with Odomzo should be assumed to indicate pregnancy untilmedical evaluation and confirmation.

Women of childbearing potential must be able to comply with effective contraceptive measures. They mustuse two methods of recommended contraception, including one highly effective method and a barriermethod, during Odomzo therapy and for 20 months after the final dose. Women of childbearing potentialwhose periods are irregular or have stopped must follow all the advice on effective contraception.

It is unknown whether sonidegib is contained in semen. Men should not father a child or donate semen whiletaking Odomzo and for at least 6 months after ending treatment. To avoid potential foetal exposure duringpregnancy, male patients, even those who have had a vasectomy, must always use a condom (withspermicide, if available) when having sex with a female partner while taking Odomzo and for 6 months afterthe final dose.

* Tubal sterilisation

* Vasectomy

* Intrauterine device (IUD)

The following are recommended barrier methods

* Any male condom (with spermicide, if available)

* Diaphragm (with spermicide, if available)

There are no data on the use of sonidegib in pregnant women. Studies in animals have shown teratogenicityand foetotoxicity (see section 5.3). Odomzo is contraindicated during pregnancy.

It is unknown whether sonidegib is excreted in human milk. Because of the potential for serious adverse drugreactions, such as serious developmental defects in breast-fed newborns/infants from sonidegib, women mustnot breast-feed while taking Odomzo or for 20 months after ending treatment (see section 5.3).

Data from studies in rats and dogs indicate that male and female fertility may be irreversibly compromisedby treatment with Odomzo (see section 5.3). Additionally, amenorrhoea has been observed in clinical studiesin women of childbearing potential (see section 4.8). Fertility preservation strategies should be discussedwith women of childbearing potential prior to starting treatment with Odomzo.

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

The phase II pivotal study evaluated the safety of Odomzo in a total of 229 adult patients with locallyadvanced or metastatic BCC. Patients were treated with Odomzo 200 mg daily (n=79) or with Odomzo800 mg daily (n=150). The median duration of treatment was 11.0 months for patients treated with Odomzoat the recommended dose of 200 mg (range 1.3 to 41.3 months). One death occurred while on treatment orwithin 30 days of the last dose taken in either metastatic BCC or locally advanced BCC patients taking

Odomzo 200 mg.

The most common adverse drug reactions occurring in ≥10% of patients treated with Odomzo 200 mg weremuscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhoea, weight decreased,decreased appetite, myalgia, abdominal pain, headache, pain, vomiting and pruritus.

The most common grade 3/4 adverse drug reactions occurring in ≥2% of patients treated with Odomzo200 mg were fatigue, weight decreased and muscle spasms.

Among adverse drug reactions reported (Table 2), the frequency was greater in patients taking Odomzo800 mg than in patients taking Odomzo 200 mg except for musculoskeletal pain, diarrhoea, abdominal pain,headache and pruritus. This was also true for grade 3/4 adverse reactions, except fatigue.

Tabulated list of adverse drug reactions

Adverse drug reactions for the recommended dose from the phase II pivotal clinical study (Table 2) are listedby Medical Dictionary for Regulatory Activities (MedDRA) version 18 system organ class. Within eachsystem organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactionsfirst. Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on thefollowing convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from theavailable data).

Table 2 Adverse drug reactions observed in the phase II pivotal study

Primary system organ class Frequency all grades

Preferred term 200 mg

Decreased appetite Very common

Dehydration Common

Dysgeusia Very common

Headache Very common

Nausea Very common

Diarrhoea Very common

Abdominal pain Very common

Vomiting Very common

Dyspepsia Common

Constipation Common

Gastro-oesophageal reflux disorder Common

Alopecia Very common

Pruritus Very common

Rash Common

Abnormal hair growth Common

Muscle spasms Very common

Musculoskeletal pain Very common

Myalgia Very common

Myopathy Common[muscular fatigue and muscular weakness]

Amenorrhoea* Very common

Fatigue Very common

Pain Very common

Weight decreased Very common

* Of the 79 patients receiving Odomzo 200 mg, 5 were women of childbearing age. Among these women,amenorrhoea was observed in 1 patient (20%).

Clinically relevant laboratory abnormalities

The most commonly reported grade 3/4 laboratory abnormalities with an incidence of ≥ 5% occurring inpatients treated with Odomzo 200 mg were lipase increase and blood CK increase (Table 3).

Table 3 Laboratory abnormalities*

Laboratory test Frequency all grades200 mg

Haematological parameters

Haemoglobin decreased Very common

Lymphocyte count decreased Very common

Biochemistry parameters

Serum creatinine increased Very common

Serum creatine phosphokinase (CK) increased Very common

Blood glucose increased Very common

Lipase increased Very common

Alanine amino transaminase (ALT) increased Very common

Aspartate amino transaminase (AST) increased Very common

Amylase increased Very common

* Based on worst laboratory value post-treatment regardless of baseline, grading by CTCAE version 4.03

Description of selected adverse drug reactions

Muscle-related adverse reactions including CK elevation

Muscle toxicity is the most clinically relevant side effect reported in patients receiving sonidegib therapy andis believed to be a class effect of inhibitors of the Hedgehog (Hh) signalling pathway. In the phase II pivotalstudy muscle spasms were the most common “muscle-related” adverse reactions, and were reported in fewerpatients in the Odomzo 200 mg group (54%) than in the Odomzo 800 mg group (69%).

Grade 3/4 increase in blood CK was reported in 8% of patients taking Odomzo 200 mg. The majority ofpatients who had grade 2 or higher CK elevations developed muscle symptoms prior to the CK elevations. Inthese patients, increases in laboratory values of CK to grade 2 and higher severity had a median time to onsetof 12.9 weeks (range 2 to 39 weeks) after initiating Odomzo therapy and a median time to resolution (tonormalisation or grade 1) of 12 days (95% CI 8 to 14 days).

One patient receiving Odomzo 200 mg experienced muscle symptoms and CK elevations above 10x ULNand required intravenous fluids, compared to 6 patients receiving Odomzo 800 mg.

In the phase II pivotal study, no reported cases of rhabdomyolysis were confirmed (defined as CK levels>10-fold above the pre-treatment or baseline level or >10x ULN if no baseline level reported plus a 1.5-foldincrease in serum creatinine from the pre-treatment or baseline level). However, one reported case in apatient treated with Odomzo 800 mg in a non-pivotal study was confirmed.

Amenorrhoea

In the phase II pivotal study, 2 (14.3%) out of 14 women of either child-bearing potential or of child-bearingage sterilised by tubal ligation developed amenorrhoea while on treatment with Odomzo 200 mg or 800 mgonce daily.

The evaluation of safety in the paediatric population is based on data from 16 adult and 60 paediatric patientsfrom Study CLDE225X2104 and 16 adult and 2 paediatric patients from Study CLDE225C2301. Themedian duration of exposure to sonidegib during Study X2104 was 97 days (range 34 to 511 days) for adultpatients and 55 days (range 2 to 289 days) for paediatric patients. The median duration of exposure tosonidegib during Study C2301 was 2.8 months (range 0.4 to 33.2 months) for adult patients and 3.5 months(range 1.3 to 5.7 months) for paediatric patients.

The toxicity of sonidegib as observed in studies C2301 and X2104 in adults was in line with the alreadyknown treatment related toxicity reported in adult patients with basal cell carcinoma.

The sonidegib-related toxicity reported in paediatric patients was similar to the results reported in adults,with the exceptions of a reduced incidence of muscle toxicity (e.g. CK elevations observed in 16.7% ofpaediatric patients compared with 50% of adults in study X2104) and the observation of post-nataldevelopment effect particularly with prolonged exposure (reported as cases of epiphyseal plate of phalanxdisorder, knee subchondral condensation of area of growth plate, physeal distal femur disorder,chondropathy, and chipped tooth).

Premature fusion of the epiphyses

Three cases (one case of cartilage injury, one case of epiphyseal disorder and one case of epiphyseal fracture)of epiphyseal growth plate disorders were reported in paediatric patients treated with sonidegib duringclinical studies but causal association with sonidegib cannot be ascertained conclusively. Premature fusion ofthe epiphyses has been reported in paediatric patients exposed to Hh (Hedgehog) pathway inhibitors.

Odomzo should not be used in paediatric patients as safety and effectiveness is not established in thispopulation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

In dose escalation studies, Odomzo was administered at doses up to 3000 mg orally once daily. Patientsshould be monitored closely for adverse events and given appropriate supportive measures in all cases ofoverdose.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XJ02

Sonidegib is an orally bioavailable inhibitor of the Hh signalling pathway. It binds to Smoothened (Smo), a

G protein-coupled receptor-like molecule that positively regulates the Hh pathway and eventually activatesand releases glioma-associated oncogene (GLI) transcription factors which induces the transcription of Hhtarget genes involved in proliferation, differentiation and survival. Aberrant Hh signalling has been linked tothe pathogenesis of several types of cancer, including basal cell carcinoma (BCC). Sonidegib binding to Smowill inhibit Hh signalling and consequently block signal transduction.

The sonidegib plasma concentration-QTc analysis showed that the upper bound of one-sided 95% confidenceinterval for QTc increase was below 5 msec at steady-state Cmax for 800 mg daily doses, which provide2.3-fold plasma exposure compared with the recommended 200 mg dose. Therefore, therapeutic doses of

Odomzo are not expected to cause clinically significant QTc prolongation. Further, sonidegib plasmaconcentrations above those achieved with the therapeutic doses were not associated with life-threateningarrhythmias or torsades de pointes.

Tumour response was independent of Odomzo dose or plasma concentration in the dose range of 200 mg to800 mg.

A phase II, randomised double-blind study of two dose levels (200 mg or 800 mg once daily) of Odomzowas conducted in 230 patients with either locally advanced basal cell carcinoma (laBCC) (n=194) ormetastatic basal cell carcinoma (mBCC) (n=36). Of the 230 patients, 16 had a diagnosis of Gorlin Syndrome(15 laBCC and 1 mBCC). Adult (≥18 years of age) patients with laBCC or mBCC who were not candidatesfor radiotherapy, surgery or other local therapies, were randomised to receive Odomzo at either 200 mg or800 mg daily until disease progression or unacceptable toxicity.

The primary efficacy endpoint of the study was objective response rate according to modified Response

Evaluation Criteria in Solid Tumours (mRECIST) in patients with laBCC and RECIST 1.1 in patients withmBCC as determined by central review. The secondary endpoints included duration of response, time totumour response and progression free survival (PFS) according to mRECIST in patients with laBCC and

RECIST 1.1 in patients with mBCC as determined by central review.

For patients with laBCC, the Independent Review Committee (IRC) Composite Overall Response wasintegrated from centrally evaluated MRI scans, digital clinical photographs and histopathology according tomRECIST. For LaBCC, multiple punch biopsies were taken each time a response assessment wasconfounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. MRI tumour response wasevaluated by RECIST 1.1. Response by digital clinical photograph was evaluated by World Health

Organization (WHO) adapted criteria [partial response (PR): ≥50% decrease in the sum of the product ofperpendicular diameters (SPD) of a lesion; complete response (CR): disappearance of all lesions; progressivedisease: ≥25% increase in the SPD of lesions]. For a composite Complete Response, all modalities used forassessment had to demonstrate absence of tumour.

Of the 230 patients randomised, 79 patients were assigned to Odomzo 200 mg. Of these 79 patients, 66(83.5%) were laBCC patients (37 [46.8%] with aggressive histology and 29 [36.7%] with non-aggressivehistology) and 13 (16.5%) were mBCC patients. The median age of all patients receiving Odomzo 200 mgwas 67 years (59.5% were >65 years of age), 60.8% were male and 89.9% Caucasian.

The majority of patients (laBCC 74%, mBCC 92%) had undergone prior therapies including surgery (laBCC73%, mBCC 85%), radiotherapy (laBCC 18%, mBCC 54%) and antineoplastic therapies (laBCC 23%,mBCC 23%).

The key efficacy results per central review and local investigator assessment are presented in Table 4.

Table 4 Efficacy overview per central review and local investigator assessment by FASa

Odomzo 200 mg

Central Local investigatorlaBCC laBCC

N=66 N=66

Objective response rate, n (%) 37 (56.1) 47 (71.2)95% CI (43.3, 68.3) (58.7, 81.7)

Best overall response, n (%)

Complete response 3 (4.5)b 6 (9.1)

Partial response 34 (51.5) 41 (62.1)

Disease stabilisation 23 (34.8) 13 (19.7)

Disease progression 1 (1.5) 1 (1.5)

Unknown 5 (7.6) 5 (7.6)

Time to tumour response (months)

Median 4.0 2.595% CI (3.8, 5.6) (1.9, 3.7)

Duration of response

No. of events* 11 22

No. censored 26 25

Median (months) 26.1 15.795% CI (NE) (12.0,20.2)

Event-free probability (%), (95% CI)6 months 86.4 (67.7, 94.7) 89.8 (74.8, 96.1)9 months 74.9 (54.4, 87.2) 80.7 (63.5, 90.4)12 months 64.9 (42.3,80.4) 71.4 (53.1, 83.6)

Progression-free survival

No. of events* 16 28

No. censored 50 38

Median (months) 22.1 19.495% CI (NE) (16.6, 23.6)

Progression-free survival probability (%), (95% CI)6 months 94.8 (84.6, 98.3) 94.7 (84.5, 98.3)12 months 82.0 (66.7, 90.7) 75.5 (60.7, 85.4)a Full analysis set included all randomised patients (intent-to-treat population).b Using only negative histology to define CR among patients who have at least a PR from other modalities(MRI or photography) resulted in a CR rate of 21.2%.

*Event refers to disease progression or death due to any reason.

FAS: Full analysis set

CI: confidence interval

NE: not estimable

Figures 1 shows the best change in target lesion size for each patient with laBCC at the dose of 200 mg percentral review.

Figure 1 Best change from baseline in the target lesions of laBCC patients per centralreview assessment by FAS

Responder (Complete Response/Partial Response)

Stable Disease

Progressive Disease

- 100 Unknown

Patient-reported outcomes were evaluated as an exploratory endpoint using the European Organisation for

Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and itsassociated head and neck cancer specific module (H&N35).

The majority of patients experienced maintenance and/or improvement in their disease-related symptoms,functioning, and health status. Time to deterioration in the pre-specified PRO scales (correspondingto >10-point worsenings without subsequent improvement) essentially mirrored the estimated PFS.

In the pivotal study, 29.1% of patients discontinued due to adverse reactions, which were mostly mild ormoderate (see section 4.8).

The European Medicines Agency has waived the obligation to submit the results of studies with Odomzo inall subsets of the paediatric population in basal cell carcinoma (see section 4.2 for information on paediatricuse).

Efficacy and safety of sonidegib have been studied in two clinical studies involving a total of 62 paediatricpatients. Study CLDE225X2104 was a Phase I/II study of sonidegib in paediatric patients with recurrent orrefractory medulloblastoma or other tumours potentially dependent on the Hedgehog (Hh) signallingpathway and adult patients with recurrent or refractory medulloblastoma. Study CLDE225C2301 was a

Phase II, multi-centre, open-label, single-arm study of the efficacy and safety of oral sonidegib in patientswith Hh-activated relapsed medulloblastoma. Results show a lack of significant efficacy despite theenrichment strategy focussed on Hh-activated medulloblastoma.

Best % change from baseline (target lesions)

Following the administration of a single dose of Odomzo (100 mg to 3000 mg) without food in patients withcancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours. Sonidegib exhibiteddose-proportional increases in AUC and Cmax over the dose range from 100 mg to 400 mg, but less thandose-proportional increases above 400 mg. There was no evidence of clearance change with repeated dosingbased on the population pharmacokinetic analysis and estimated accumulation at steady state was 19-foldirrespective of dose. Steady state was reached approximately 4 months after starting sonidegib. The averagesteady state Ctrough for 200 mg was 830 ng/ml (range 200 to 2400 ng/ml) in cancer patients. Compared to thefasted state, the Cmax and AUC of Odomzo 800 mg was increased 7.8- and 7.4-fold, respectively when thedose was given with a high-fat meal. Compared to the fasted state, the Cmax and AUC of Odomzo 200 mgwas increased 2.8- and 3.5-fold, respectively, when the dose was given with a light meal. Compared to thefasted state, the Cmax and AUC of Odomzo 200 mg increased 1.8- and 1.6-fold, respectively, when amoderate meal was taken 2 hours before the administration. A moderate meal taken 1 hour after theadministration of Odomzo 200 mg provided similar exposures compared to the fasted state.

Based on a population pharmacokinetic analysis of 351 patients who received oral doses of Odomzo in thedose range of 100 mg to 3000 mg, the apparent steady-state volume of distribution (Vss/F) was 9170 litres.

Steady-state level of sonidegib in the skin was 6-fold higher than in plasma.

Sonidegib was highly bound to human plasma proteins (human serum albumin and alpha-1 acidglycoprotein) in vitro (>97%), and binding was not concentration-dependent from 1 ng/ml to 2500 ng/ml.

Based on in vitro data, sonidegib is not a substrate of P-gp, BCRP or multi-resistance protein 2 (MRP2).

Sonidegib did not inhibit apical efflux transporters, P-gp or MRP2, hepatic uptake transporters OATP1B1 or

OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the organic cation uptaketransporters OCT1 or OCT2 at clinically relevant concentrations.

Sonidegib is primarily metabolised by CYP3A4. Unchanged sonidegib represented 36% of circulatingradioactivity and the major circulating metabolite (45% of parent exposure) identified in plasma is thehydrolysis product of sonidegib and is pharmacologically inactive. All the metabolites were deemed 4 to90 times less potent than sonidegib.

Sonidegib and its metabolites are eliminated primarily by the hepatic route with 93.4% of the administereddose recovered in the faeces and 1.95% recovered in urine. Unchanged sonidegib in faeces represented88.7% of the administered dose and was not detectable in urine. The elimination half-life (t1/2) of sonidegibestimated from population pharmacokinetic modeling was approximately 28 days.

The pharmacokinetics of sonidegib were examined in subjects with mild (Child-Pugh class A; n=8),moderate (Child-Pugh class B; n=8) or severe (Child-Pugh class C; n=9) hepatic impairment and in 8 healthysubjects with normal hepatic function. Cmax of sonidegib after a single oral 800 mg dose was 20%, 21% and60% lower in mild, moderate and severe hepatic impairment, respectively, compared to normal hepaticfunction. AUCinf of sonidegib was 40%, 22% and 8% lower, respectively. AUClast was 35% lower in mildhepatic impairment, 14% higher in moderate hepatic impairment and 23% lower in severe hepaticimpairment. No dose adjustment is necessary in patients with hepatic impairment.

The effect of renal impairment on the systemic exposure of sonidegib has not been studied. Since sonidegibis not renally excreted, no change in systemic exposure is anticipated in patients with renal impairment. Apopulation pharmacokinetic analysis did not find significant influence of renal function (creatinine clearance>27 ml/min) on the apparent clearance (CL/F) of sonidegib suggesting that dose adjustment is not necessaryin patients with renal impairment.

Effect of age, weight and gender

Population pharmacokinetic analyses showed that there are no clinically relevant effects of age (range testedfrom 20-93 years, mean 61 years), body weight (range tested 42-181 kg, mean 77 kg), gender, or creatinineclearance (range tested 27.3-290 ml/min, mean 92.9 ml/min) on the systemic exposure of sonidegib.

Effect of ethnicity

The Cmax and AUCinf of sonidegib in Japanese healthy subjects were 1.56 and 1.68-fold higher, respectively,than those seen in Western healthy subjects for a single dose of 200 mg.

Sonidegib was evaluated in rats and dogs.

General toxicology

The majority of adverse effects of sonidegib can be attributed to its pharmacological mechanism of action ondevelopmental pathways and effects in rats and dogs were similar. Most effects occurred close to theintended human exposures. These effects observed at clinically relevant exposures include closure of bonegrowth plates, effects on growing teeth, effects on the male and female reproductive tract, atrophy of the hairfollicles with alopecia, gastrointestinal toxicity with body weight loss and effects on lymph nodes. Atexposures well above the clinical exposure, an additional target organ was the kidney.

Carcinogenesis and mutagenesis

Sonidegib was not genotoxic in studies conducted in vitro and in vivo. No carcinogenic potential wasidentified in rat and mice carcinogenicity studies. However, exposure levels were far below clinical exposurelevels in rats, and around clinical exposure levels in mice.

Sonidegib was shown to be foetotoxic in rabbits, as evidenced by abortion and/or complete resorption offoetuses and teratogenic resulting in severe malformations at very low exposure. Teratogenic effectsincluded vertebral, distal limb and digit malformations, severe craniofacial malformations and other severemidline defects. Foetotoxicity in rabbits was also seen at very low maternal exposure. There was reducedfertility at low exposure in female rats. For sonidegib treated male rats, exposure at approx. 2-fold theclinical exposure did not impact male fertility.

Environmental risk assessment studies have shown that sonidegib may pose a risk for surface water (seesection 6.6).

Crospovidone Type A

Lactose monohydrate

Magnesium stearate

Poloxamer 188

Silica, colloidal anhydrous

Sodium laurilsulfate

Gelatin

Iron oxide red (E172)

Titanium dioxide (E171)

Iron oxide black (E172)

Propylene glycol (E1520)

Shellac

Not applicable.

5 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

10 x 1 hard capsule in PCTFE/PVC/Alu perforated unit-dose blisters.

Each pack contains either 10 or 30 hard capsules.

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 872132JH Hoofddorp

Netherlands

EU/1/15/1030/001

EU/1/15/1030/002

Date of initial authorisation: 14 August 2015

Date of latest renewal: 20 May 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu