Isturisa 1 mg film coated tablets

Isturisa is indicated for the treatment of endogenous Cushing's syndrome in adults.

Treatment should be initiated and supervised by physicians experienced in endocrinology or internal medicine and with access to the appropriate facilities for monitoring of biochemical responses since the dose must be adjusted to meet the patient's therapeutic needs, based on the normalisation of cortisol levels.

Posology

The recommended starting dose is 2 mg osilodrostat twice daily. For patients of Asian ancestry, a reduced starting dose of 1 mg twice daily is recommended (see section 5.2).

The dose can be gradually titrated (initially by dose increments of 1 or 2 mg) based on individual response and tolerability, with the aim to achieve normal cortisol levels. It is recommended that cortisol levels (e.g. 24-hour urinary free cortisol, serum/plasma cortisol) be monitored every 1-2 weeks until adequate clinical response is maintained. Thereafter, less frequent monitoring may be considered as clinically indicated, unless there are reasons for additional monitoring (see sections 4.4 and 4.5). Increases in dose should not occur more frequently than once every 1-2 weeks and should be guided by the results of cortisol assessments and by the individual clinical response.

The dose of osilodrostat should be decreased or treatment temporarily interrupted if cortisol levels are below the lower limit of normal, or if there is a rapid decrease in cortisol levels to the lower part of the normal range, or if the patient has signs or symptoms suggestive of hypocortisolism (see section 4.4). Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lower limit of normal in the absence of glucocorticoid substitution. Management of other suspected adverse reactions at any time during treatment may also require a temporary dose reduction or temporary interruption of treatment.

The usual maintenance dose in clinical studies varied between 2 and 7 mg twice daily.

The maximum recommended dose of Isturisa is 30 mg twice daily.

If a dose is missed, the patient should take the prescribed dose at the next scheduled time; the next dose should not be doubled.

Elderly (65 years or above)

There is no evidence to suggest that dose adjustment is required in patients aged 65 years or above. However, data on the use of osilodrostat in this population are limited and Isturisa should therefore be used with caution in this age group.

Renal impairment

No dose adjustment is required for patients with renal impairment (see section 5.2). Urinary free cortisol (UFC) levels should be interpreted with caution in patients with moderate to severe renal impairment, due to reduced UFC excretion. Alternative methods for cortisol monitoring should be considered in these patients.

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A). For patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 1 mg twice daily. For patients with severe hepatic impairment (Child-Pugh C), the recommended starting dose is 1 mg once daily in the evening, with initial up-titration to 1 mg twice daily (see section 5.2).

Data on use in patients with hepatic impairment is limited. More frequent monitoring of adrenal function may be required in patients with hepatic impairment during dose titration.

Paediatric population

The safety and efficacy of Isturisa in patients less than 18 years of age have not yet been established. No data are available.

Method of administration

Oral use.

Isturisa can be taken with or without food.

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

Hypocortisolism

Inhibition of cortisol synthesis by osilodrostat has led to hypocortisolism-related events such as cortisol withdrawal syndrome (symptomatic decrease of cortisol levels, but still above the lower limit of the normal range) and adrenal insufficiency (cortisol levels below the normal range).

Cortisol levels should be monitored at regular intervals (see section 4.2), since hypocortisolism-related events can occur at any time during treatment. Additional monitoring is recommended especially during conditions of increased cortisol demand, such as physical or psychological stress, or during changes in concomitant medications that may affect osilodrostat exposure (see section 4.5). It is recommended to use laboratory methods that do not exhibit significant cross-reactivity with cortisol precursors such as 11-deoxycortisol that may increase during osilodrostat treatment.

Patients should be alerted to the signs and symptoms associated with hypocortisolism (e.g. nausea, vomiting, fatigue, abdominal pain, loss of appetite and dizziness).

Symptomatic patients should be monitored for hypotension, hyponatraemia, hyperkalaemia and/or hypoglycaemia. If hypocortisolism is suspected, cortisol levels should be measured and temporary dose reduction or interruption of osilodrostat considered. If necessary, corticosteroid substitution should be initiated. Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lower limit of normal in the absence of glucocorticoid substitution.

QTc prolongation

In a thorough QT study, osilodrostat was associated with a dose-dependent QT interval prolongation (mean maximum estimated QTcF increase by +5.3 ms at the highest recommended dose of 30 mg) which may cause cardiac arrhythmias (see section 5.1). Adverse reactions of QT prolongation and clinically relevant ECG findings have been reported in clinical studies.

An ECG should be performed prior to the start of Isturisa treatment, within one week after treatment initiation, and as clinically indicated thereafter. If the QTc interval exceeds 480 ms prior to or during treatment, cardiology consultation is recommended. Temporary dose reduction or interruption may be required.

Any hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to Isturisa administration and electrolyte levels should be monitored periodically during therapy.

Isturisa should be used with caution and the benefit-risk carefully weighed in patients with risk factors for QT prolongation such as:

- congenital long QT syndrome,

- significant cardiovascular disease (including congestive heart failure, recent myocardial infarction, unstable angina, sustained ventricular tachycardia, advanced heart block and clinically significant bradyarrhythmias), and

- concomitant medicinal products known to prolong the QT interval (see section 4.5).

If Isturisa is used in patients with these risk factors, more frequent ECG monitoring is recommended.

Corticotroph tumour growth

Discontinuation of osilodrostat treatment should be considered in patients who develop MRI-verified corticotroph tumour invasiveness during treatment.

Concomitant use with strong enzyme inhibitors and inducers

Caution and closer monitoring are advised when co-administered medicinal products that strongly inhibit or induce multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.5), as they may affect osilodrostat exposure and may result in a risk of adverse events (due to a potential increase in exposure) or of decreased efficacy (due to a potential decrease in exposure).

Women of childbearing potential

Isturisa may cause foetal harm. Pregnancy status should be verified in women of childbearing potential prior to the initiation of Isturisa, and these patients should be advised of a potential risk to the foetus and of the need to use effective contraception during treatment and for at least one week after stopping treatment (see section 4.6).

Potential pharmacodynamic interactions

Co-administration of osilodrostat with other therapies known to affect the QT interval can lead to QT prolongation in patients with known cardiac rhythm disorders (see sections 4.4 and 5.1). A washout period should be considered when switching from other products known to affect the QT interval such as pasireotide or ketoconazole.

Effects of other medicinal products on the pharmacokinetics of osilodrostat

The potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low (see section 5.2).

Strong enzyme inhibitors

Caution is advised when co-administered medicinal products that strongly inhibit multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.4).

Strong enzyme inducers

Caution is advised when co-administered medicinal products that strongly induce multiple enzymes (e.g. rifampin) are introduced or discontinued during osilodrostat treatment (see section 4.4).

Effects of osilodrostat on the pharmacokinetics of other medicinal products

Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes and transporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme or transporter substrates with a narrow therapeutic index. Available interaction data is summarised below (see also section 5.2).

Clinical studies

In a healthy volunteer study (n=20) using a single dose of 50 mg osilodrostat and a probe drug cocktail, osilodrostat was found to be a mild inhibitor of CYP2D6 and CYP3A4/5, a mild to moderate inhibitor of CYP2C19, and a moderate inhibitor of CYP1A2.

- CYP2D6 – AUC geometric mean ratio of 1.5 for dextromethorphan (CYP2D6 substrate) when dosed with osilodrostat compared to when dosed alone.

- CYP3A4 – AUC geometric mean ratio of 1.5 for midazolam (CYP3A4 substrate) when dosed with osilodrostat compared to when dosed alone.

- CYP2C19 – AUC geometric mean ratio of 1.9 for omeprazole (CYP2C19 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of time-dependent inhibition has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP2C19 substrates with a narrow therapeutic index.

- CYP1A2 – AUC geometric mean ratio of 2.5 for caffeine (CYP1A2 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of CYP1A2 induction has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP1A2 substrates with a narrow therapeutic index such as theophylline and tizanidine.

In a healthy volunteer study (n=24), osilodrostat (30 mg twice daily for 7 days before concomitant administration with a combined oral contraceptive containing 0.03 mg ethinyl oestradiol and 0.15 mg levonorgestrel and continued for another 5 days) did not have a clinically meaningful effect on the AUC and C_max of ethinyl estradiol (geometric mean ratio: 1.03 and 0.88, respectively) and AUC of levonorgestrel (geometric mean ratio: 1.02). The C_max of levonorgestrel fell slightly outside the bioequivalence acceptance range (geometric mean ratio: 0.86; 90% confidence interval : 0.737-1.00). The effects of a longer induction period and an interaction with other hormonal contraceptives have not been studied (see also sections 4.4 and 4.6).

In vitro data

In vitro data for osilodrostat and its major metabolite M34.5 suggest a potential for both inhibition and induction for CYP1A2, CYP2B6 and CYP3A4/5, a potential for time-dependent inhibition of CYP2C19, and an inhibitory potential for CYP2E1 and UGT1A1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these enzymes.

In vitro data for osilodrostat and its major metabolite M34.5 suggest an inhibitory potential for OATP1B1, OCT1, OCT2, OAT1, OAT3 and MATE1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these transporters.

Women of childbearing potential

Based on preclinical data, osilodrostat may cause foetal harm when administered to a pregnant woman. A pregnancy test before initiating treatment is recommended in women of childbearing potential. Women of childbearing potential have to use effective contraception during and for at least one week after treatment. If hormonal contraceptives other than the oral combination of ethinylestradiol and levonorgestrel are used, an additional barrier method of contraception is recommended (see section 4.5).

Pregnancy

There are no or limited amount of data from the use of osilodrostat in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Isturisa should not be used during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether osilodrostat or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Isturisa and for at least one week after treatment.

Fertility

There is no information on the effect of osilodrostat on human fertility. Animal studies have shown effects on the menstrual cycle and reduced female fertility in rats (see section 5.3).

Isturisa may have a minor influence on the ability to drive and use machines. Patients should be warned about the potential for dizziness and fatigue (see section 4.8) and should be advised not to drive or use machines if these symptoms occur.

Summary of the safety profile

The most frequent adverse reactions reported in the pivotal phase III study with osilodrostat were adrenal insufficiency (51%), fatigue (44%), oedema (21%), vomiting (22%), nausea (42%) and headache (34%).

The most serious adverse reaction associated with the use of osilodrostat is adrenal insufficiency (see also sections 4.2 and 4.4).

Tabulated list of adverse reactions

Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Table 1 Adverse drug reactions

Description of selected adverse reactions

CYP11B1 inhibition by osilodrostat is associated with adrenal steroid precursor accumulation and testosterone increases. In a clinical study with osilodrostat, mean testosterone levels in female patients increased from high normal at baseline to above the upper limit of the normal range. The increases reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism or acne in a subset of patients.

ACTH values above 10-fold upper limit of normal were observed in some Cushing's disease patients treated with osilodrostat in the clinical studies (see section 5.1) and may be associated with cortisol values below the lower limit of normal.

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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness and syncope.

In case of suspected overdosage, Isturisa should be interrupted, cortisol levels checked, and if necessary corticosteroid supplementation initiated. Close surveillance may be necessary including monitoring of the QT interval, blood pressure, glucose, fluid and electrolyte balance until the patient's condition is stable.

Pharmacotherapeutic group: Anticorticosteroids, ATC code: H02CA02

Mechanism of action

Osilodrostat is a cortisol synthesis inhibitor. It potently inhibits 11β -hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

CYP11B1 inhibition is associated with the accumulation of precursors such as 11-deoxycortisol and acceleration of adrenal biosynthesis including androgens. In Cushing's disease, the fall in plasma cortisol concentration also stimulates ACTH secretion, via the feedback mechanism which accelerates steroid biosynthesis (see section 4.8).

Pharmacodynamic effects

In a thorough QT study (n=86 male and female healthy volunteers) with osilodrostat, the maximum QTcF interval duration differences to placebo were 1.73 ms (90% CI: 0.15, 3.31) at the 10 mg dose and 25.38 ms (90% CI: 23.53, 27.22) at a supratherapeutic dose of 150 mg. Based on an interpolation of these results, the mean maximum prolongation at the highest recommended dose of 30 mg is estimated to be +5.3 ms.

Clinical efficacy and safety

The efficacy and safety of osilodrostat in patients with Cushing's disease were evaluated in a prospective phase III study (study C2301) that used a randomised withdrawal design. The study consisted of a 26-week open-label period of single-arm osilodrostat treatment, followed by an 8-week randomised withdrawal period in which patients were randomised in 1:1 ratio to either osilodrostat or placebo and a subsequent osilodrostat open-label period.

The eligibility criteria included Cushing's disease (with confirmation of the pituitary source of excess adrenocorticotrophic hormone), and a mean urinary free cortisol (mUFC, derived from three 24-hour urine collections) value greater than 1.5 times the upper limit of normal (ULN) at screening.

A total of 137 adult patients were enrolled. The mean age was 41.2 years, and the majority of patients were female (77%). Seven patients were aged 65 years or older. Prior therapy included pituitary surgery in 88% of patients and prior medical therapy in 75% of patients. The mean and median baseline mUFC levels were 1006.0 nmol/24 h and 476.4 nmol/24 h, respectively (ULN: 138 nmol/24 h). Co-morbidities at baseline included hypertension (67.9% of patients), obesity (29.9%), diabetes mellitus (21.9%) and osteoporosis (27.7%).

Patients received a starting dose of 2 mg osilodrostat twice daily and the dose could be up-titrated based on individual response and tolerability during an initial 12-week period. Patients with no further dose increases during the following 12 weeks and with a mUFC ≤ ULN at week 24 were randomised in a 1:1 ratio at week 26 to receive either osilodrostat or matching placebo for 8 weeks (double-blind randomised withdrawal period), followed by open-label osilodrostat for the remainder of the study. At week 26, 71 patients were randomised in a 1:1 ratio to continue receiving osilodrostat (n=36) or to switch to placebo (n=35). Patients who were not eligible for randomisation at week 24 (n=47) continued on open-label osilodrostat treatment.

The primary objective was to compare the proportion of complete responders at week 34 (the end of the 8-week randomised withdrawal period) between patients randomised to continued active treatment and placebo. For the primary endpoint, a complete response was defined as a mUFC value ≤ ULN at week 34. Patients whose dose was increased during the randomised withdrawal period or who discontinued randomised treatment were considered non-responders. The key secondary endpoint was the complete response rate at week 24. Patients with dose increases between weeks 12 and 24 and patients with no valid mUFC assessment at week 24 were counted as non-responders for the key secondary endpoint.

The study met its primary and key secondary endpoints (Table 2).

Median mUFC levels decreased to 62.5 nmol/24 h (-84.1% change from baseline, n=125) at week 12, to 75.5 nmol/24 h (-82.3%, n=125) at week 24 and to 63.3 nmol/24 h (-87.9%, n=108) at week 48.

Table 2 Key results: Phase III study in Cushing's disease patients (study C2301)

Improvements were observed in cardiovascular and metabolic parameters (Table 3) and 85.6% of patients with available assessments showed an improvement in at least one physical feature of Cushing's disease at week 48.

Table 3 Cardiovascular and metabolic parameters

Osilodrostat treatment also resulted in an improvement in patient-reported outcomes. Improvements from baseline above the established minimal important difference (MID) were observed for Cushing's QoL (total score, Physical Problems subscale and Psychosocial Issues subscale), EQ-5D Utility index and BDI-II (depression) scores.

The mean Cushing QoL total score improved from 42.2 at baseline to 58.3 (+14.1; +52.4% change from baseline) at week 48.

The efficacy of osilodrostat was also assessed in study C1201 in nine adult Japanese patients with non-pituitary causes of Cushing's syndrome. The study enrolled patients with adrenal adenoma (n=5), ectopic corticotropin syndrome (n=3) and ACTH-independent macronodular adrenal hyperplasia (n=1), and consisted of a 12-week dose titration period (starting dose 2 mg twice daily), a 36-week maintenance period and an optional long-term extension. At week 12 (primary endpoint) a complete response (mUFC ≤ ULN) was observed in 6 patients (66.7%) and a partial response (mUFC decrease by at least 50%) in one additional patient (11.1%). The median average dose used in the study was 2.6 mg/day (range 1.3-7.5 mg/day). The mean duration of treatment in this study was 24 weeks, and long-term exposure was limited.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Isturisa in one or more subsets of the paediatric population in adrenal cortical hyperfunction (see section 4.2 for information on paediatric use).

Absorption

Osilodrostat is a highly soluble, highly permeable compound (BCS class 1). It is rapidly absorbed (t_max ~1 h) and oral absorption in humans is assumed to be nearly complete. Steady state is reached by day 2.

Co-administration with food did not affect absorption to a clinically significant extent. In a healthy volunteer study (n=20), the administration of a single dose of 30 mg osilodrostat with a high-fat meal resulted in a modest reduction of AUC and C_max by 11% and 21%, respectively, and the median t_max was delayed from 1 to 2.5 hours.

No clinically relevant accumulation was observed in clinical studies. An accumulation ratio of 1.3 was estimated for the 2 to 30 mg dose range.

Distribution

The median apparent volume of distribution (V_z/F) of osilodrostat is approximately 100 litres. Protein binding of osilodrostat and of its major metabolite M34.5 is low (less than 40%) and concentration-independent. The osilodrostat blood-to-plasma concentration ratio is 0.85.

Osilodrostat is not a substrate for OATP1B1 or OATP1B3 transporters.

Biotransformation

In a human ADME study in healthy subjects following the administration of a single dose of 50 mg [¹⁴C]-osilodrostat, metabolism was deemed the most important clearance pathway for osilodrostat since ~80% of the dose was excreted as metabolites. The three main metabolites in plasma (M34.5, M16.5 and M24.9) represented 51%, 9% and 7% of the dose, respectively. Both M34.5 and M24.9 have longer half-lives than osilodrostat and some accumulation is expected with twice-daily dosing. The decrease in the contribution of osilodrostat to the radioactivity AUC with time post-dose was found to coincide closely with a corresponding increase in the contribution of M34.5.

Thirteen metabolites were characterised in the urine, with the three main metabolites being M16.5, M22 (an M34.5 glucuronide) and M24.9, with 17, 13 and 11% of the dose, respectively. The formation of the major urinary metabolite M16.5 (direct N-glucuronide) was catalysed by UGT1A4, 2B7 and 2B10. Less than 1% of the dose was excreted as M34.5 (di-oxygenated osilodrostat) in the urine but 13% of the dose was identified as M22 (M34.5-glucuronide). The formation of M34.5 was non-CYP- mediated.

Multiple CYP enzymes and UDP glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes more than 25% to the total clearance. The main CYP enzymes involved in osilodrostat metabolism are CYP3A4, 2B6 and 2D6. Total CYP contribution is 26%, total UGT contribution is 19% and non-CYP non-UGT mediated metabolism was shown to contribute to ~50% of total clearance. In addition, osilodrostat showed a high intrinsic permeability, low efflux ratio and modest impact of inhibitors on the efflux ratio in vitro. This suggests that the potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low.

In vitro data indicate that the metabolites do not contribute to the pharmacological effect of osilodrostat.

Elimination

The elimination half-life of osilodrostat is approximately 4 hours.

In an ADME study, the majority (91%) of the radioactive dose of osilodrostat was eliminated in the urine, with only a minor amount eliminated in the faeces (1.6% of dose). The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.

Linearity/non-linearity

Exposure (AUC_inf and C_max) increased more than dose-proportionally over the therapeutic dose range.

Drug-drug interactions (see also section 4.5)

In vitro data indicate that neither osilodrostat nor its major metabolite M34.5 inhibits the following enzymes and transporters at clinically relevant concentrations: CYP2A6, CYP2C8, CYP2C9, UGT2B7, P-gp, BCRP, BSEP, MRP2, OATP1B3 and MATE2-K. Since the exposure of M34.5 has not yet been determined after repeated dosing, the clinical relevance of the in vitro drug-drug interaction results for M34.5 is unknown.

Special populations

Hepatic impairment

In a phase I study in 33 subjects with varying degrees of hepatic function using a single dose of 30 mg osilodrostat, AUC_inf was 1.4- and 2.7-fold higher in the moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment cohorts, respectively. C_max was 15 and 20% lower in the moderate and severe cohorts. The terminal half-life increased to 9.3 hours and 19.5 hours in the moderate and severe cohorts. Mild hepatic impairment (Child-Pugh A) did not influence exposure to any significant extent. The absorption rate was not affected by the degree of hepatic impairment.

Renal impairment

In a phase I study in 15 subjects with varying degrees of renal function using a single dose of 30 mg osilodrostat, comparable systemic exposure was seen in subjects with severe renal impairment, end-stage renal disease and normal renal function.

Race/ethnicity and bodyweight

The relative bioavailability was approximately 20% higher in Asian patients compared to other ethnicities. Body weight was not shown to be a major determinant of this difference.

Age and gender

Age and gender had no significant impact on osilodrostat exposure in adults. The number of elderly patients in clinical studies was limited (see section 4.2).

Repeat dose toxicity

In repeat dose toxicity studies conducted in mice, rats and dogs, the central nervous system, liver, female reproductive organs, and the adrenal gland were the primary target organs. The NOAEL for hepatic, reproductive organ and adrenal effects in long-term (26- and 39-week) studies was at least four-fold human clinical exposure based on AUC. CNS findings (aggression, hypersensitivity to touch and increased or decreased activity) were noted in the rat, mouse and dog. The NOAEL for the CNS effects was approximately 2-fold human free C_max based on the most sensitive species.

Carcinogenicity and mutagenicity

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation do not indicate a relevant risk in humans. In rat and mice carcinogenicity studies, an increased incidence of hepatocellular adenoma/carcinoma (at lower doses in males than females), and neoplastic changes of thyroid follicular adenoma/carcinoma (in male rats only) were observed. The findings are likely rodent specific and considered not relevant to humans.

Fertility and reproductive toxicity

Reproductive studies in rabbits and rats demonstrated embryotoxicity, foetotoxicity (increased resorptions and decreased foetal viability, decreased foetal weights, external malformations, and visceral and skeletal variations) and teratogenicity at maternally toxic doses. The NOAEL was 10-fold human exposure (AUC) in a pre- and postnatal developmental study, and 8- to 73-fold human exposure (AUC) in a rat fertility and early embryonic development study. The maternal and foetal NOAEL in the rabbit embryofoetal development study was 0.6-fold human exposure (AUC).

Juvenile toxicity

The findings in juvenile rat toxicity studies were largely consistent with those observed in adult rat studies. Delayed sexual maturation was noted at high doses with no effects on overall reproductive performance or parameters after a 6-week recovery period. There were no effects on long bone growth or behavioural performance.

Tablet core

Cellulose, microcrystalline Mannitol

Croscarmellose sodium Magnesium stearate Silica, colloidal anhydrous

Film coat

Hypromellose

Titanium dioxide (E171) Macrogol

Talc

1 mg tablet

Iron oxide yellow (E172) Iron oxide red (E172)

Not applicable.

3 years.

Do not store above 25° C. Store in the original package in order to protect from moisture.

Alu/Alu blister of 10 tablets.

Packs containing 60 tablets (6 blisters of 10 tablets).

No special requirements.

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