Orkambi 100 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets

Orkambi 100 mg/125 mg film-coated tablets

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

Orkambi 200 mg/125 mg film-coated tablets

Each film-coated tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Orkambi 100 mg/125 mg film-coated tablets

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

Orkambi 200 mg/125 mg film-coated tablets

Pink, oval-shaped tablets (dimensions 14 × 8.4 × 6.8 mm) printed with “2V125” in black ink on one side.

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

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

For standard dosing recommendations see Table 1.

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

Special populations

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 Orkambi 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 at a reduced dose (see sections 4.4, 4.8, and 5.2).

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

Renal impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using Orkambi 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).

Elderly people

The safety and efficacy of Orkambi in patients aged 65 years or older have not been eva luated.

Paediatric population

The safety and efficacy of Orkambi in children aged less than 6 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. Patients may start taking Orkambi on any day of the week.

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

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 events

Respiratory events (e.g., chest discomfort, dyspnoea, and respiration abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory events were seen more frequently in patients with percent predicted FEV₁ (ppFEV₁) <40, and may lead to drug discontinuation. 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 events

Elevated transaminases have been reported in patients with CF receiving lumacaftor/ivacaftor. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin.

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), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests closely followed until the abnormalities resolve. 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.

The drug interaction profile for lumacaftor 200 mg/ivacaftor 250 mg every 12 hours is considered to be the same as that for lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, based on exposure at the indicated doses.

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 drug 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 the Table mostly derives from in vitro studies. The recommendations provided under “Clinical comment” in Table 3 are based on drug interaction studies, clinical relevance, or predicted interactions due to elimination pathways. Drug interactions that have the most clinical relevance are listed first.

Paediatric population

Interaction studies have only been performed in adults.

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

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. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (see section 5.3).

Ivacaftor, which is one of the active components of Orkambi, has a minor influence on the ability to drive or 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.