COMETRIQ 20 mg hard capsules

COMETRIQ 80 mg hard capsules

One hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib.

For the full list of excipients, see section 6.1.

Hard capsule.

The hard capsules are grey with “XL184 20mg” printed in black on the body of the capsule. The capsule contains an off-white to white powder.

The hard capsules are orange with “XL184 80mg” printed in black on the body of the capsule. The capsule contains an off-white to white powder.

COMETRIQ is indicated for the treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.

For patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision (see important information in sections 4.4 and 5.1).

Therapy with COMETRIQ should be initiated by a physician experienced in the administration of anticancer medicinal products.

Posology

The recommended dose of COMETRIQ is 140 mg once daily, taken as one 80 mg orange capsule and three 20 mg grey capsules. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

It should be expected that a majority of patients treated with COMETRIQ will require one or more dose adjustments (reduction and/or interruption) due to toxicity. Patients should therefore be closely monitored during the first eight weeks of therapy (see section 4.4).

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of COMETRIQ therapy. When dose reduction is necessary, it is recommended to reduce to 100 mg daily, taken as one 80 mg orange capsule and one 20 mg grey capsule, and then to 60 mg daily, taken as three 20 mg grey capsules.

Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities.

Dose reductions are recommended for events that, if persistent, could become serious or intolerable.

As most events can occur early in the course of treatment, the physician should eva luate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), and gastrointestinal (GI) events (abdominal or mouth pain, mucosal inflammation, constipation, diarrhoea, vomiting).

The occurrence of some serious adverse reactions (like GI fistula) might be dependent on the cumulative dose and might present in a later stage of treatment.

If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.

Concomitant medicinal products

Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided (see sections 4.4 and 4.5).

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.

Elderly patients

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended. However, a trend in increased rate of SAEs has been observed in subjects aged 75 years and older.

Race

There is little experience with cabozantinib in non-White patients.

Patients with renal impairment

Cabozantinib should be used with caution in patients with renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.

Patients with hepatic impairment

Cabozantinib is not recommended for use in patients with hepatic impairment, since there is limited data in patients with heatic impairment, and safety and efficacy have not been established.

Patients with cardiac impairment

There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made.

Paediatric population

The safety and efficacy of cabozantinib in children aged <18 years have not yet been established. No data are available.

Method of administration

The capsules should be swallowed whole and not opened. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking COMETRIQ.

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

Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated patients in the pivotal clinical trial. Two dose reductions were required in 41% of patients. The median time to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is therefore recommended during the first eight weeks of therapy (see section 4.2).

Perforations, fistulas, and intra-abdominal abscesses

Serious GI perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic cavity (including mediastinum) should be carefully eva luated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas. Non-GI fistula should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should be discontinued in patients who experience a GI perforation or a GI or non-GI fistula.

Thromboembolic events

Events of venous thromboembolism and events of arterial thromboembolism have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Haemorrhage

Hemorrhage has been observed with cabozantinib. Patients who have evidence of involvement of the trachea or bronchi by tumour or a history of haemoptysis prior to treatment initiation should be carefully eva luated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients with serious haemorrhage or recent haemoptysis.

Wound complications

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.

Hypertension

Hypertension has been observed with cabozantinib. All patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Osteonecrosis

Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. For invasive dental procedures, cabozantinib treatment should be held at least 28 days prior to scheduled surgery, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.

Palmar-plantar erythrodysaesthesia syndrome

Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.

Proteinuria

Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES) has been observed with cabozantinib. Cabozantinib treatment should be discontinued in patients with RPLS.

Prolongation of QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be used with caution.

CYP3A4 inducers and inhibitors

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see sections 4.2 and 4.5).

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC₅₀ = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.

MRP2 inhibitors

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution.

Effect of other medicinal products on cabozantinib

CYP3A4 inhibitors and inducers

Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore co-administration of strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.

Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John's Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.

Gastric pH modifying agents

Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.

MRP2 inhibitors

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.

Effect of cabozantinib on other medicinal products

The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC₅₀ = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception,” they should be used together with another method, such as a barrier method (see section 4.5).

Pregnancy

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.

Breast-feeding

It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). Both men and women should be advised to seek advice and consider fertility preservation before treatment.

Cabozantinib has a minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

Summary of safety profile

The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia.

The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, neutropenia, thrombocytopenia, hypophosphatemia, hypoalbumenia, and hyperbilirubinemia.

Tabulated summary of adverse reactions

Adverse reactions are listed in Table 1 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported with cabozantinib

Description of selected adverse reactions

A thyroid stimulating hormone (TSH) value above normal after first dose was observed in 57% of patients on cabozantinib versus 19% of patients on placebo (regardless of baseline values). Ninety-two percent of patients on the cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormones prior to first dose.

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 - 15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was observed in a controlled clinical study in cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects had a QTcF >500 ms.

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not been established.

In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to be treated symptomatically.

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE26.

Mechanism of action

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, and metastatic progression of cancer. Cabozantinib was eva luated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including RET, the GAS6 receptor (AXL), the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).

Pharmacodynamic effects

Cabozantinib exhibited dose-related tumour growth inhibition, tumor regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Efficacy with cabozantinib was observed in medullary thyroid cancer patients with wild-type or mutant RET.

Clinical data in medullary thyroid cancer

A multi-center, randomized double-blind study comparing cabozantinib (N = 219) with placebo (N = 111) was conducted in patients with unresectable locally advanced or metastatic MTC and documented radiographic disease progression within 14 months prior to study entry. The primary objective was to compare progression-free survival (PFS) in patients receiving cabozantinib versus patients receiving placebo. The secondary objectives were to compare overall response rate (ORR) and overall survival (OS). Centralized, independent, blinded review of the imaging data was used in the assessment of PFS and ORR. Patients were treated until disease progression or unacceptable toxicity.

The result of the PFS analysis, based on the central review RECIST assessment, demonstrated a statistically significant difference in the duration of PFS with cabozantinib versus placebo: the median duration was 11.2 months for subjects in the cabozantinib arm versus 4.0 months for subjects in the placebo arm (stratified Hazard Ratio [HR] = 0.28; 95% CI: 0.19, 0.40; p<0.0001; Figure 1). The PFS results were consistent across all baseline and demographic subgroups eva luated, including prior therapy with tyrosine kinase inhibitors (which may have consisted of agents targeting pathways associated with anti-angiogenesis), RET mutational status (including subjects documented not to have RET mutations), prior anticancer or radiotherapy status, or the existence of bone metastases.

The ORR was 27.9% and 0% for subjects in the cabozantinib arm and placebo arm, respectively (p<0.0001; Table 2). The median duration of objective responses was 14.6 months (95% CI: 11.1, 17.5) for subjects in the cabozantinib arm.

An interim administrative analysis of OS performed including 75% of total deaths required for the final analysis shows a trend for prolonged OS in the cabozantinib arm compared to placebo: stratified HR (95% CI) 0.83 (0.60, 1,14); median (months) 26.0 cabozantinib vs. 20.3 placebo.

Figure 1: Kaplan Meier curve of progression free survival

Table 2: Summary of key efficacy findings

^a Response = CR + PR

^b Disease Control Rate = SD+ ORR

^c Includes patients who were eva luable for response

RET mutation status

Of the 215 subjects with sufficient data to determine mutational status, 78.6% (n=169) were classified as RET mutation positive, and 21.4% (n=46) were classified as RET mutation negative. For an additional 115 subjects the RET mutational status could not be determined or was unclear. All three subgroups showed increased PFS in the cabozantinib arm compared to the placebo arm (HRs of 0.23, 0.53, and 0.30 for RET mutation positive, negative, and unknown subgroups, respectively). The objective response rates measured in these subgroups were generally consistent with the PFS results, with the RET mutation positive, negative, and unknown subgroups showing tumour response rates of 32%, 22%, and 25%, respectively.

Further genetic analysis showed that a small proportion of patients harboured somatic tumour mutations in HRAS, KRAS, or NRAS. These patients (n=16) showed significant prolongation of PFS (HR of 0.15) and an objective response rate of 31%. RET mutation negative patients with no evidence of RAS mutation (n=33) showed a decreased PFS benefit on cabozantinib (HR of 0.87) and a lower response rate of 18% compared to other mutational subgroups.

A relationship between prolonged PFS and significant improvement in OS (HR 0.53, p=0.0179) has been demonstrated only in the subgroup of RET M918T mutation positive patients (n=81/219 cabozantinib arm). OS has not yet been analysed in other RET and/or RAS mutation subgroups.

Figure 2. Kaplan-Meier Analysis of OS Among Subjects with a RET M918T Mutation

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with cabozantinib in one or more subsets of the paediatric population in the treatment of malignant solid tumours (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 5 hours post-dose.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased C_max and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution (V/F) is approximately 349 L (SE: ± 2.73%).

Biotransformation

Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.

Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalyzed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction).

Elimination

The plasma terminal half-life of cabozantinib in single dose studies in healthy volunteers is approximately 120 hours. Mean clearance (CL/F) at steady-state in cancer patients was estimated to be 4.4 L/hr in a population PK analysis. Within a 48-day collection period after a single dose of ¹⁴C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

Renal impairment

A difference in PK in patients with renal impairment cannot be excluded, as data in this population are not yet available.

Hepatic impairment

A difference in PK in patients with hepatic impairment cannot be excluded, as data in this population are not yet available.

Race

No data are available to determine a difference in PK based on race.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. Carcinogenicity studies have not been performed.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observe in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.

Juvenile rats (comparable to a >2 year old pediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and bile duct hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. eva luations in juvenile rats (comparable to a <2 year old pediatric population) have not been performed.

Capsule content

Microcrystalline cellulose

Croscarmellose sodium

Sodium starch glycoloate

Silica colloidal anhydrous

Stearic acid

Capsule shell

Gelatin

Black iron oxide (E172) (20 mg capsules only)

Red iron oxide (E172) (80 mg capsules only)

Titanium dioxide (E171)

Printing ink

Shellac

Black iron oxide (E172)

Propylene glycol

Not applicable.

3 years.

Do not store above 25 °C.

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

PVC/PE/PCTFE-Al blisters with foil backing, sealed into a secondary heat-sealed card packaging.

Blister cards containing either:

7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply)

21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply)

28 day pack containing:

56 capsules (4 blister cards of: 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for a 28 day supply)

112 capsules (4 blister cards of: 21 x 20mg and 7 x 80 mg) (140 mg/day dose for a 28 day supply)

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

TMC Pharma Services Ltd.

Lodge Farm Barn

Elvetham Park Estate

Fleet Road

Hartley Wintney

Hampshire

RG27 8AS

United Kingdom

 EU/1/13/890/002
7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply)
EU/1/13/890/003
21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply)
EU/1/13/890/005
56 capsules (4 blister cards of: 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for 28 day supply)
EU/1/13/890/006
112 capsules (4 blister cards of: 21 x 20mg and 7 x 80 mg) (140 mg/day dose for 28 day supply)  

Date of first authorisation: 21 March 2014

18/12/2014

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.