4.1. Therapeutic indications

Kaftrio granules are indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in paediatric patients aged 2 to less than 6 years who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see section 5.1).

4.2. Posology and method of administration

Kaftrio should only be prescribed by healthcare professionals 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 at least one F508del mutation using a genotyping assay (see section 5.1).

Posology

Paediatric patients aged 2 to less than 6 years should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 2 to less than 6 years

Age

Weight

Morning dose

Evening dose

2 to less than 6 years

<14 kg

One sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules

One sachet of ivacaftor 59.5 mg granules

≥14 kg

One sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules

One sachet of ivacaftor 75 mg granules

The morning and evening dose should be taken approximately 12 hours apart, with fat‑containing food (see Method of administration).

Missed dose

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule.

If more than 6 hours have passed since:

• the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time.

OR

• the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.

Morning and evening doses should not be taken at the same time.

Concomitant use of CYP3A inhibitors

When co‑administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be reduced as in Table 2 (see sections 4.4 and 4.5).

Concomitant use of ciprofloxacin is not expected to have a clinically relevant effect on the exposure of ivacaftor/tezacaftor/elexacaftor; therefore, no dose adjustment is recommended with concomitant use of ciprofloxacin (see section 4.5).

Table 2: Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors

Moderate CYP3A Inhibitors

Strong CYP3A Inhibitors

Alternate each day:

• One sachet of ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX) granules on the first day

• One sachet of ivacaftor (IVA) granules on the next day

No evening sachet of IVA granules.

One sachet of IVA/TEZ/ELX granules twice a week, approximately 3 to 4 days apart.

No evening sachet of IVA granules.

Special populations

Hepatic impairment

Treatment of patients aged 2 to less than 6 years with moderate hepatic impairment (Child‑Pugh Class B) is not recommended. For patients aged 2 to less than 6 years with moderate hepatic impairment, the use of Kaftrio should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks. If used, it should be used with caution at a reduced dose (see Table 3).

Studies have not been conducted in patients with severe hepatic impairment (Child‑Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. Patients with severe hepatic impairment should not be treated with Kaftrio.

No dose adjustment is recommended for patients with mild (Child‑Pugh Class A) hepatic impairment (see Table 3) (see sections 4.4, 4.8, and 5.2).

Table 3: Recommendation for use in patients aged 2 to less than 6 years with hepatic impairment

Mild

(Child‑Pugh Class A)

Moderate

(Child‑Pugh Class B)

Severe

(Child‑Pugh Class C)

No dose adjustment

Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, as follows:

• Days 1‑3: one sachet of IVA/TEZ/ELX granules each day

• Day 4: no dose

• Days 5‑6: one sachet of IVA/TEZ/ELX granules each day

• Day 7: no dose

Repeat above dosing schedule each week.

The evening dose of the IVA granules should not be taken.

Should not be used

Renal impairment

No dose adjustment is recommended for patients with mild and moderate renal impairment. There is no experience in patients with severe renal impairment or end‑stage renal disease (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Kaftrio in combination with ivacaftor 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. The entire contents of each sachet of granules should be mixed with one teaspoon (5 mL) of age‑appropriate soft food or liquid and the mixture completely consumed. Food or liquid should be at room temperature or below. Each sachet is for single use only. Once mixed, the product has been shown to be stable for one hour, and therefore should be ingested during this period. Some examples of soft food or liquids include pureed fruits or vegetables, yogurt, water, milk, or juice. A fat‑containing meal or snack should be consumed just before or after dosing.

Kaftrio should be taken with fat‑containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats (see section 5.2).

Food or drink containing grapefruit should be avoided during treatment with Kaftrio (see section 4.5).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Elevated transaminases and hepatic injury

In a patient with cirrhosis and portal hypertension liver failure leading to transplantation has been reported while receiving IVA/TEZ/ELX in combination with ivacaftor. IVA/TEZ/ELX in combination with IVA should be used with caution in patients with pre‑existing advanced liver disease (e.g., cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment (see sections 4.2, 4.8, and 5.2).

Elevated transaminases are common in patients with CF and have been observed in some patients treated with IVA/TEZ/ELX in combination with IVA. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter. For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered. In the event of ALT or AST >5 x the upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x ULN, dosing should be interrupted, and laboratory tests closely followed until the abnormalities resolve. Following the resolution of transaminase elevations, the benefits and risks of resuming treatment should be considered (see sections 4.2, 4.8, and 5.2).

Hepatic impairment

Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks. If used, it should be used with caution at a reduced dose (see Table 3).

Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2).

Renal impairment

There is no experience in patients with severe renal impairment/end‑stage renal disease therefore caution is recommended in this population (see sections 4.2 and 5.2).

Patients after organ transplantation

IVA/TEZ/ELX in combination with IVA 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 commonly used immunosuppressants.

Rash events

The incidence of rash events was higher in females than in males, particularly in females taking hormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with IVA/TEZ/ELX in combination with IVA and hormonal contraceptives should be considered. Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combination with IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).

Mood disturbances

Effects on mood and behaviour have been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation. Patients (and caregivers) should be alerted about the need to monitor for symptoms including new onset or worsening of anxiety or low mood, sleep disturbance, and forgetfulness. In some children, persistent behavioural changes have been observed while taking IVA/TEZ/ELX. Inform patients to seek medical advice as soon as possible if these symptoms present.

Consider whether treatment discontinuation is appropriate.

Elderly

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults. Dose recommendations are based on the pharmacokinetic profile and knowledge from studies with TEZ/IVA in combination with IVA, and IVA monotherapy (see sections 4.2 and 5.2).

Interactions with medicinal products

CYP3A inducers

Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease by the concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of IVA/TEZ/ELX and IVA; therefore, co‑administration with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

Exposures of ELX, TEZ and IVA are increased when co‑administered with strong or moderate CYP3A inhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Cataracts

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

Excipients with known effect

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA

CYP3A inducers

ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy. Co‑administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co‑administration with strong CYP3A inducers; therefore, co‑administration with strong CYP3A inducers is not recommended (see section 4.4).

Examples of strong CYP3A inducers include:

• rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort (Hypericum perforatum)

CYP3A inhibitors

Co‑administration with itraconazole, a strong CYP3A inhibitor, increased ELX AUC by 2.8‑fold and TEZ AUC by 4.0‑ to 4.5‑fold. When co‑administered with itraconazole and ketoconazole, IVA AUC increased by 15.6‑fold and 8.5‑fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co‑administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of strong CYP3A inhibitors include:

• ketoconazole, itraconazole, posaconazole and voriconazole

• telithromycin and clarithromycin

Simulations indicated that co‑administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9‑ to 2.3‑fold. Co‑administration of fluconazole increased IVA AUC by 2.9‑fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co‑administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of moderate CYP3A inhibitors include:

• fluconazole

• erythromycin

Co‑administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

Ciprofloxacin

IVA/TEZ/ELX was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had no clinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevant effect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitant administration of IVA/TEZ/ELX with ciprofloxacin.

Potential for interaction with transporters

In vitro studies showed that ELX is a substrate for the efflux transporters P‑gp and Breast Cancer Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to ELX is not expected to be affected significantly by concomitant use of P‑gp and BCRP inhibitors due to its high intrinsic permeability and low likelihood of being excreted intact.

In vitro studies showed that TEZ is a substrate for the uptake transporter OATP1B1 and efflux transporters P‑gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expected to be affected significantly by concomitant inhibitors of OATP1B1, P‑gp, or BCRP due to its high intrinsic permeability and low likelihood of being excreted intact. However, exposure to M2‑TEZ (TEZ metabolite) may be increased by inhibitors of P‑gp. Therefore, caution should be used when P‑gp inhibitors (e.g., ciclosporin) are used with IVA/TEZ/ELX.

In vitro studies showed that IVA is not a substrate for OATP1B1, OATP1B3, or P‑gp. IVA and its metabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low likelihood of being excreted intact, co‑administration of BCRP inhibitors is not expected to alter exposure of IVA and M1‑IVA, while any potential changes in M6‑IVA exposures are not expected to be clinically relevant.

Medicinal products affected by ELX, TEZ and/or IVA

CYP2C9 substrates

IVA may inhibit CYP2C9; therefore, monitoring of the international normalised ratio (INR) during co‑administration of warfarin with IVA/TEZ/ELX and IVA is recommended. Other medicinal products for which exposure may be increased include glimepiride and glipizide; these medicinal products should be used with caution.

Potential for interaction with transporters

Co‑administration of IVA or TEZ/IVA with digoxin, a sensitive P‑gp substrate, increased digoxin AUC by 1.3‑fold, consistent with weak inhibition of P‑gp by IVA. Administration of IVA/TEZ/ELX and IVA may increase systemic exposure of medicinal products that are sensitive substrates of P‑gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P‑gp with a narrow therapeutic index such as ciclosporin, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used.

ELX and M23‑ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2‑fold. Co‑administration with IVA/TEZ/ELX in combination with IVA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3 substrate. In study 445‑102, mild increases in mean total bilirubin were observed (up to 4.0 µmol/L change from baseline). This finding is consistent with the in vitro inhibition of bilirubin transporters OATP1B1 and OATP1B3 by ELX and M23‑ELX.

ELX and IVA are inhibitors of BCRP. Co‑administration of IVA/TEZ/ELX, and IVA may increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When used concomitantly with substrates of BCRP, appropriate monitoring should be used.

Hormonal contraceptives

IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. IVA/TEZ/ELX and IVA is not expected to have an impact on the efficacy of oral contraceptives.

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 ELX, TEZ or IVA in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of IVA/TEZ/ELX during pregnancy.

Breast‑feeding

It is unknown whether ELX, TEZ, IVA, or their metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of ELX, TEZ and IVA into the milk of lactating female rats (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast‑feeding or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures. ELX and IVA had an effect on fertility in rats (see section 5.3).

4.7. Effects on ability to drive and use machines

IVA/TEZ/ELX in combination with IVA has a minor influence on the ability to drive or use machines. Dizziness has been reported in patients receiving IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness 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 experienced by patients aged 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%) and upper respiratory tract infection (11.9%).

Serious adverse reactions of rash were reported in 3 (1.5%) patients treated with IVA/TEZ/ELX in combination with IVA compared to 1 (0.5%) in placebo.

Tabulated list of adverse reactions

Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class and frequency: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4: Adverse reactions

MedDRA System Organ Class

Adverse Reactions

Frequency

Infections and infestations

Upper respiratory tract infection*, Nasopharyngitis

very common

Rhinitis*, Influenza*

common

Metabolism and nutrition disorders

Hypoglycaemia*

common

Psychiatric disorders

Low mood

not known

Nervous system disorders

Headache*, Dizziness*

very common

Ear and labyrinth disorders

Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, Vestibular disorder

common

Ear congestion

uncommon

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain, Nasal congestion*

very common

Rhinorrhoea*, Sinus congestion, Pharyngeal erythema, Abnormal breathing*

common

Wheezing*

uncommon

Gastrointestinal disorders

Diarrhoea*, Abdominal pain*

very common

Nausea, Abdominal pain upper*, Flatulence*

common

Hepatobiliary disorders

Transaminase elevations

very common

Alanine aminotransferase increased*, Aspartate aminotransferase increased*

common

Liver injury†, Total bilirubin elevations†

not known

Skin and subcutaneous tissue disorders

Rash*

very common

Acne*, Pruritus*

common

Reproductive system and breast disorders

Breast mass

common

Breast inflammation, Gynaecomastia, Nipple disorder, Nipple pain

uncommon

Investigations

Bacteria in sputum

very common

Blood creatine phosphokinase increased*

very common

Blood pressure increased*

uncommon

*Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.

†Liver injury (ALT and AST and total bilirubin elevations) reported from post‑marketing data with IVA/TEZ/ELX in combination with IVA. This also included liver failure leading to transplantation in a patient with pre‑existing cirrhosis and portal hypertension. Frequency cannot be estimated from the available data.

Safety data from the following studies were consistent with the safety data observed in study 445‑102.

• A 4‑week, randomised, double‑blind, active‑controlled study in 107 patients aged 12 years and older (study 445‑103).

• A 192‑week, open‑label safety and efficacy study (study 445‑105) in 506 patients rolled over from studies 445‑102 and 445‑103.

• An 8‑week, randomised, double‑blind, active‑controlled study in 258 patients aged 12 years and older (study 445‑104).

• A 24‑week, open‑label study (study 445‑106) in 66 patients aged 6 to less than 12 years.

• A 192‑week, two‑part (part A and part B), open‑label safety and efficacy study (study 445‑107) in patients aged 6 years and older who rolled over from study 445‑106.

• A 24‑week, open‑label study (study 445‑111) in 75 patients aged 2 to less than 6 years.

Description of selected adverse reactions

Transaminase elevations

In study 445‑102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the ULN was 1.5%, 2.5% and 7.9% in IVA/TEZ/ELX‑treated patients and 1.0%, 1.5% and 5.5% in placebo‑treated patients. The incidence of adverse reactions of transaminase elevations was 10.9% in IVA/TEZ/ELX‑treated patients and 4.0% in placebo‑treated patients.

Post‑marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).

Rash events

In study 445‑102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in IVA/TEZ/ELX‑ and 6.5% in placebo‑treated patients. The rash events were generally mild to moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX‑treated patients and 4.8% in males and 8.3% in females in placebo‑treated patients. In patients treated with IVA/TEZ/ELX, the incidence of rash events was 20.5% in females taking hormonal contraceptive and 13.6% in females not taking hormonal contraceptive (see section 4.4).

Increased creatine phosphokinase

In study 445‑102, the incidence of maximum creatine phosphokinase >5 x the ULN was 10.4% in IVA/TEZ/ELX‑ and 5.0% in placebo‑treated patients. The observed creatine phosphokinase elevations were generally transient and asymptomatic and many were preceded by exercise.

Increased blood pressure

In study 445‑102, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for IVA/TEZ/ELX‑treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo‑treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg on at least two occasions was 5.0% and 3.0%, respectively in IVA/TEZ/ELX‑treated patients compared with 3.5% and 3.5%, respectively in placebo‑treated patients.

Paediatric population

The safety data of IVA/TEZ/ELX in combination with IVA in studies 445‑102, 445‑103, 445‑104, 445‑106 and 445‑111 was evaluated in 228 patients between 2 to less than 18 years of age. The safety profile is generally consistent among paediatric and adult patients.

During study 445‑106 in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 0.0%, 1.5%, and 10.6%, respectively. No IVA/TEZ/ELX‑treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations (see section 4.4).

During study 445‑111 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 1.3%, 2.7%, and 8.0% respectively. No IVA/TEZ/ELX‑treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations (see section 4.4).

Other special populations

With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with IVA was generally similar across all subgroups of patients, including analysis by age, baseline percent predicted forced expiratory volume in one second (ppFEV1), and geographic regions.

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 IVA/TEZ/ELX. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.