ORKAMBI 100 MG / 125 MG FILM-COATED TABLETS - Summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Orkambi 100 mg/125 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Pink, oval-shaped tablets (dimensions 14 × 7.6 × 4.9 mm) printed with “1V125” in black ink on one side.

4.1 Therapeutic indications

Orkambi tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Orkambi should only be prescribed by physicians with experience in the treatment of CF. If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of the F508del mutation on both alleles of the CFTR gene.

Posology

Table 1: Dosing recommendations in patients aged 6 years and older

Patients may start treatment on any day of the week.

This medicinal product should be taken with fat-containing food. A fat-containing meal or snack should be consumed just before or just after dosing (see section 5.2).

Missed dose

If less than 6 hours have passed since the missed dose, the scheduled dose should be taken with fat-containing food. If more than 6 hours have passed, the patient should be instructed to wait until the next scheduled dose. A double dose should not be taken to make up for the forgotten dose.

Concomitant use of CYP3A inhibitors

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking Orkambi. However, when initiating treatment in patients taking strong CYP3A inhibitors, reduce the dose to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 6 to 11 years; lumacaftor 200 mg/ivacaftor 125 mg for patients aged 12 years and older) for the first week of treatment to allow for the steady state induction effect of lumacaftor. Following this period, the recommended daily dose should be continued.

If treatment is interrupted for more than one week and then re-initiated while taking strong CYP3A inhibitors, reduce the dose to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 6 to 11 years; lumacaftor 200 mg/ivacaftor 125 mg for patients aged 12 years and older) for the first week of treatment re-initiation. Following this period, the recommended daily dose should be continued (see section 4.5).

Special populations

Renal impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). For patients with moderate hepatic impairment (Child-Pugh Class B), a dose reduction is recommended.

There is no experience of the use of the medicinal product in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, after weighing the risks and benefits of treatment, Orkambi should be used with caution in patients with severe hepatic impairment, at a reduced dose (see sections 4.4, 4.8 and 5.2).

For dose adjustments for patients with hepatic impairment see Table 2.

Table 2: Dose adjustment recommendations for patients with hepatic impairment

Paediatric population

The safety and efficacy of Orkambi in children aged less than 2 years have not yet been established. No data are available (see section 5.1).

Method of administration

For oral use.

Patients should be instructed to swallow the tablets whole. Patients should not chew, break, or dissolve the tablets.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Patients with CF who are heterozygous for the F508del mutation in the CFTR gene

Lumacaftor/iva­caftor is not effective in patients with CF who have the F508del mutation on one allele plus a second allele with a mutation predicted to result in a lack of CFTR production or that is not responsive to ivacaftor in vitro (see section 5.1).

Patients with CF who have a gating (Class III) mutation in the CFTR gene

Lumacaftor/iva­caftor has not been studied in patients with CF who have a gating (Class III) mutation in the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since the exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor, lumacaftor/iva­caftor should not be used in these patients.

Respiratory adverse reactions

Respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) were more common during initiation of lumacaftor/iva­caftor therapy. Serious respiratory events were seen more frequently in patients with percent predicted forced expiratory volume in 1 second (ppFEV1) <40, and may lead to discontinuation of the medicinal product. Clinical experience in patients with ppFEV1 < 40 is limited and additional monitoring of these patients is recommended during initiation of therapy (see section 4.8). A transient decline in FEV1 has also been observed in some patients following initiation of lumacaftor/iva­caftor. There is no experience of initiating treatment with lumacaftor/iva­caftor in patients having a pulmonary exacerbation and initiating treatment in patients having a pulmonary exacerbation is not advisable.

Effect on blood pressure

Increased blood pressure has been observed in some patients treated with lumacaftor/iva­caftor. Blood pressure should be monitored periodically in all patients during treatment (see section 4.8).

Patients with advanced liver disease

Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. Worsening of liver function in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension receiving lumacaftor/iva­caftor. Lumacaftor/iva­caftor should be used with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If lumacaftor/iva­caftor is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced (see sections 4.2, 4.8, and 5.2).

Hepatobiliary adverse reactions

Elevated transaminases have been commonly reported in patients with CF receiving lumacaftor/iva­caftor. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin. Transaminase elevations have been observed more frequently in paediatric patients than in adult patients (see section 4.8).

Because an association with liver injury cannot be excluded, assessments of liver function tests (ALT, AST and bilirubin) are recommended before initiating lumacaftor/iva­caftor, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered.

In the event of significant elevation of ALT or AST, with or without elevated bilirubin (either ALT or AST > 5 x the upper limit of normal [ULN], or ALT or AST > 3 x ULN with bilirubin > 2 x ULN and/or clinical jaundice), dosing with lumacaftor/iva­caftor should be discontinued and laboratory tests closely followed until the abnormalities resolve. A thorough investigation of potential causes should be conducted and patients should be followed closely for clinical progression. Following resolution of transaminase elevations, the benefits and risks of resuming dosing should be considered (see sections 4.2, 4.8, and 5.2).

Interactions with medicinal products

Substrates of CYP3A

Lumacaftor is a strong inducer of CYP3A. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended (see section 4.5).

Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi (see section 4.5).

Strong CYP3A inducers

Ivacaftor is a substrate of CYP3A4 and CYP3A5. Therefore, co-administration with strong CYP3A inducers (e.g., rifampicin, St. John’s wort [Hypericum perforatum]) is not recommended (see section 4.5).

Renal impairment

Caution is recommended while using lumacaftor/iva­caftor in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).

Cataracts

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with lumacaftor/iva­caftor and ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded (see section 5.3). Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with lumacaftor/iva­caftor.

Patients after organ transplantation

Lumacaftor/iva­caftor has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 for interactions with immunosuppressants.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Based on exposure and indicated doses, the interaction profile is considered to be the same for all strengths and pharmaceutical for­ms.

Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. There is potential for other medicinal products to affect lumacaftor/iva­caftor when administered concomitantly, and also for lumacaftor/iva­caftor to affect other medicinal products.

Potential for other medicinal products to affect lumacaftor/iva­caftor

Inhibitors of CYP3A

Co-administration of lumacaftor/iva­caftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy.

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/iva­caftor. However, when initiating lumacaftor/iva­caftor in patients taking strong CYP3A inhibitors, the dose should be adjusted (see sections 4.2 and 4.4).

No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors.

Inducers of CYP3A

Co-administration of lumacaftor/iva­caftor with rifampicin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, co-administration of lumacaftor/iva­caftor is not recommended with strong CYP3A inducers (see sections 4.2 and 4.4).

No dose adjustment is recommended when used with moderate or weak CYP3A inducers.

Potential for lumacaftor/iva­caftor to affect other medicinal products

CYP3A substrates

Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/iva­caftor therapy is expected to be strong CYP3A induction. Therefore, concomitant use of lumacaftor/iva­caftor with CYP3A substrates may decrease the exposure of these substrates (see section 4.4).

P-gp substrates

In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of lumacaftor/iva­caftor with P-gp substrates (e.g., digoxin) may alter the exposure of these substrates.

CYP2B6 and CYP2C substrates

Interaction with CYP2B6 and CYP2C substrates has not been investigated in vivo. In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; however, inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of lumacaftor/iva­caftor may alter (i.e., either increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decrease the exposure of CYP2C19 substrates, and substantially decrease the exposure of CYP2B6 substrates.

Potential for lumacaftor/iva­caftor to interact with transporters

In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP). Co-administration of Orkambi with medicinal products that inhibit BCRP may increase plasma lumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3. Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinal products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of such medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, and organic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3.

Established and other potentially significant interactions

Table 3 provides the established or predicted effect of lumacaftor/iva­caftor on other medicinal products or the effect of other medicinal products on lumacaftor/iva­caftor. The information reported in Table 3 mostly derives from in vitro studies. The recommendations provided under “Clinical comment” in Table 3 are based on interaction studies, clinical relevance, or predicted interactions due to elimination pathways. Interactions that have the most clinical relevance are listed first.

Table 3: Established and other potentially significant interactions – dose recommendations for use of lumacaftor/iva­caftor with other

_______medicinal products

Note: t = increase, J, = decrease, = = no change; LUM = lumacaftor;

IVA = ivacaftor.

* Based on clinical interaction studies. All other interactions shown are predicted.

False positive urine tests for THC

There have been reports of false positive urine screening tests for tetrahydrocan­nabinol (THC) in patients receiving Orkambi. An alternative confirmatory method should be considered to verify results.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of lumacaftor/iva­caftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicate direct or indirect harmful effects with respect to developmental and reproductive toxicity, whereas effects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionary measure, it is preferable to avoid the use of lumacaftor/iva­caftor during pregnancy unless the clinical condition of the mother requires treatment with lumacaftor/iva­caftor.

Breast-feeding

It is unknown whether lumacaftor and/or ivacaftor and metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of both lumacaftor and ivacaftor into the milk of lactating female rats. As such, risks to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from lumacaftor/

ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impaired fertility and reproductive performance indices in male and female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Ivacaftor, which is one of the active components of Orkambi, has a minor influence on the ability to drive and use machines. Ivacaftor may cause dizziness (see section 4.8).

Patients experiencing dizziness while taking Orkambi should be advised not to drive or use machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions in Phase 3 clinical studies were dyspnoea (14.0% versus 7.8% on placebo), diarrhoea (11.0% versus 8.4% on placebo), and nausea (10.2% versus 7.6% on placebo).

Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations, cholestatic hepatitis and hepatic encephalopathy.

Tabulated list of adverse reactions

Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (trials 1 and 2) in patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to 11 years (trial 7), who are homozygous for the F508del mutation in the CFTR gene are presented in Table 4 and are listed by system organ class and frequency. Adverse reactions observed with ivacaftor alone are also provided in Table 4. Adverse reactions are ranked under the MedDRA frequency classification: very common

(> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (frequency cannot be estimated using the available data).

Table 4: Adverse reactions in lumacaftor/iva­caftor-treated patients and in patients treated with ivacaftor alone

* Adverse reactions and frequencies observed in patients in clinical studies with ivacaftor monotherapy t 1 patient out of 738

* 2 patients out of 738

The safety data from 1,029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene treated with lumacaftor/iva­caftor for up to an additional 96 weeks in the long-term safety and efficacy rollover study (trial 3) were similar to the 24-week, placebo-controlled studies (see section 5.1).

Description of selected adverse reactions

Hepatobiliary adverse reactions

During trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 0.8%, 2.0%, and 5.2%; and 0.5%, 1.9%, and 5.1% in lumacaftor/iva­caftor- and placebo-treated patients, respectively. The incidence of transaminase-related adverse reactions was 5.1% and 4.6% in lumacaftor/iva­caftor-treated patients and those who received placebo, respectively. Seven patients who received lumacaftor/iva­caftor had liver-related serious adverse reactions with elevated transaminases, including 3 with concurrent elevation in total bilirubin. Following discontinuation of lumacaftor/iva­caftor, liver function tests returned to baseline or improved substantially in all patients (see section 4.4).

Among 7 patients with pre-existing cirrhosis and/or portal hypertension who received lumacaftor/iva­caftor in the placebo-controlled, Phase 3 studies, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of lumacaftor/iva­caftor (see section 4.4).

Post-marketing cases of liver function decompensation including liver failure leading to death have been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with lumacaftor/iva­caftor (see section 4.4).

Respiratory adverse reactions

During trials 1 and 2, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) was 26.3% in lumacaftor/iva­caftor-treated patients compared to 17.0% in patients who received placebo. The incidence of these adverse reactions was more common in patients with lower pre-treatment FEV1. Approximately three-quarters of the events began during the first week of treatment, and in most patients the events resolved without dosing interruption. The majority of adverse reactions were mild or moderate in severity, non-serious and did not result in treatment discontinuation (see section 4.4).

During a 24-week, open label, Phase 3b clinical study (trial 5) in 46 patients aged 12 years and older with advanced lung disease (ppFEV1 < 40) [mean ppFEV1 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory adverse reactions was 65.2%. In the subgroup of 28 patients who were initiated at the full dose of lumacaftor/iva­caftor (2 tablets every 12 hours), the incidence was 71.4%, and in the 18 patients who were initiated at a reduced dose of lumacaftor/iva­caftor (1 tablet every 12 hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the patients who were initiated lumacaftor/iva­caftor at the full dose, one patient had a serious respiratory adverse reaction, three patients subsequently had their dose reduced, and three patients discontinued treatment. No serious respiratory adverse reactions, dose reductions or discontinuations were seen in patients who were initiated at the half dose (see section 4.4).

Menstrual abnormalities

During trials 1 and 2, the incidence of combined menstrual abnormalities (amenorrhoea, dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and polymenorrhoea) was 9.9 % in lumacaftor/iva­caftor-treated female patients and 1.7% in placebo-treated females. These menstrual events occurred more frequently in the subset of female patients who were taking hormonal contraceptives (25.0%) versus patients who were not taking hormonal contraceptives (3.5%) (see section 4.5). Most of these reactions were mild or moderate in severity and non-serious. In lumacaftor/iva­caftor-treated patients, approximately two-thirds of these reactions resolved, and the median duration was 10 days.

Increased blood pressure

During trials 1 and 2, adverse reactions related to increased blood pressure (e.g., hypertension, blood pressure increased) were reported in 0.9% (7/738) of patients treated with lumacaftor/iva­caftor and in no patients who received placebo.

In patients treated with lumacaftor/iva­caftor (mean baseline 114 mmHg systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.1 mmHg and 1.8 mmHg, respectively. In patients who received placebo (mean baseline 114 mmHg systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 0.9 mmHg and 0.9 mmHg, respectively.

The proportion of patients who experienced a systolic blood pressure value > 140 mmHg or a diastolic blood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated with lumacaftor/iva­caftor, respectively, compared with 1.6% and 0.5% in patients who received placebo (see section 4.4).

Paediatric population

Safety data were evaluated in 60 patients aged 2 to 5 years (trial 8), 161 patients aged 6 to 11 years (trials 6 and 7) and in 194 patients aged 12 to 17 years with CF who are homozygous for the F508del mutation and who received lumacaftor/iva­caftor in clinical studies. Patients aged 12 to 17 years were included in trials 1 and 2.

The safety profile in these paediatric patients is generally consistent with that in adult patients.

Long-term safety data from a 96-week rollover extension study in 57 patients aged 2 years and older who were homozygous for the F508del mutation in the CFTR gene were generally consistent with the 24-week parent study in patients aged 2 to 5 years (trial 8) and safety data in patients aged 6 to 11 years.

Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and older who were homozygous for the F508del mutation in the CFTR gene (trial 9) were generally consistent with the 24-week parent studies in patients aged 6 to 11 years (trial 6 and trial 7).

Description of selected adverse reactions for patients aged 6 to 11 years Hepatobiliary adverse reactions

During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to 11 years (trial 6), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and >3 x ULN was 5.3%, 8.8%, and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/iva­caftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years (trial 7), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 1.0%, 4.9%, and 12.6% in the lumacaftor/iva­caftor patients, and 2.0%, 3.0%, and 7.9% in the placebo-treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the lumacaftor/iva­caftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

Respiratory adverse reactions

During the 24-week, open-label Phase 3 clinical study (trial 6) in 58 patients aged 6 to 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58).

During the 24-week, placebo-controlled Phase 3 clinical study (trial 7) in patients aged 6 to 11 years (mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in lumacaftor/iva­caftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4–6 hours post-dose was –7.7 on day 1 and –1.3 on day 15 in lumacaftor/iva­caftor patients. The post-dose decline was resolved by week 16.

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:

Yellow Card Scheme

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

4.9 Overdose

No specific antidote is available for overdose with lumacaftor/iva­caftor. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Adverse reactions that occurred at an increased incidence of > 5% in the supratherapeutic dose period compared with the therapeutic dose period were headache, generalised rash, and increased transaminase.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Cellulose, microcrystalline

Croscarmellose sodium Hypromellose acetate succinate

Povidone (K30)

Sodium laurilsulfate

Magnesium stearate

Coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol (3350)

Talc

Carmine (E120)

Brilliant blue FCF aluminium lake (E133)

Indigo carmine aluminium lake (E132)

Printing ink

Shellac

Iron oxide black (E172)

Propylene glycol

Ammonia solution, concentrated

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister consisting of PolyChloroTri­FluoroEthylene (PCTFE)/PolyVinyl Chloride (PVC) with a paper-backed aluminium foil lidding.

Pack containing 112 (4 packs of 28) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Vertex Pharmaceuticals (Europe) Limited

2 Kingdom Street

London, W2 6BD

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 22352/0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021