Special Warning : אזהרת שימוש

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 ORKA_100_125-200_125-SPC-0524-V1                     Page 4 of 31
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).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with lumacaftor/ivacaftor, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders. In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

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).

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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’.

Effects on Driving

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.