Orkambi

ORKAMBI is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the

• Reduce dosage in patients with moderate or severe hepatic impairment. (
  2.2 Dosage Adjustment for Patients with Hepatic Impairment

  For dosage adjustment for patients with hepatic impairment, refer to Table 2.

  Studies have not been conducted 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, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment

  [see

  Dosage and Administration (2.1),

  Use in Specific Populations (8.6)

  ,

  Clinical Pharmacology (12.3)

  , and

  Patient Counseling Information (17)

  ]

  .

  Table 2: Recommended Dosage for Patients with Hepatic Impairment

  	Age Group	Weight	Morning Dose	Evening Dose
  Mild (Child-Pugh Class A)	1 through 2 years	7 kg to <9 kg	1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules	1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules
  		9 kg to <14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules
  	2 through 5 years	<14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules
  	6 through 11 years	-	2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose)	2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose)
  	12 years and older	-	2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose)	2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose)
  Moderate (Child-Pugh Class B)	1 through 2 years	7 kg to <9 kg	1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules	1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules every other day
  		9 kg to <14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules every other day
  	2 through 5 years	<14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules every other day
  	6 through 11 years	-	2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose)	1 tablet of lumacaftor 100 mg/ivacaftor 125 mg
  	12 years and older	-	2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose)	1 tablet of lumacaftor 200 mg/ivacaftor 125 mg
  Severe (Child-Pugh Class C)	1 through 2 years	7 kg to <9 kg	1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granulesor less frequently.	N/A
  		9 kg to <14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules
  	2 through 5 years	<14 kg	1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules
  		≥14 kg	1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules
  	6 through 11 years	-	1 tablet of lumacaftor 100 mg/ivacaftor 125 mg	1 tablet of lumacaftor 100 mg/ivacaftor 125 mg
  	12 years and older	-	1 tablet of lumacaftor 200 mg/ivacaftor 125 mg	1 tablet of lumacaftor 200 mg/ivacaftor 125 mg
  ,
  8.6 Hepatic Impairment

  No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening is recommended for patients aged 6 years and older with moderate hepatic impairment (Child-Pugh Class B). A dose reduction to 1 packet of oral granules in the morning daily and 1 packet of oral granules in the evening every other day is recommended for patients aged 1 to 5 years old with moderate hepatic impairment (Child-Pugh Class B).

  Studies have not been conducted 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, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment

  [see

  Warnings and Precautions (5.1)

  ,

  Adverse Reactions (6.1)

  ,

  Clinical Pharmacology (12.3)

  , and

  Patient Counseling Information (17)

  ]

  .
  ,
  12.3 Pharmacokinetics

  The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor.

  Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF

  	Drug	Cmax (μg/mL)	t½Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects. (h)	AUC0-12h (μg∙h/mL)
  Lumacaftor 400 mg q12h/ Ivacaftor 250 mg q12h	Lumacaftor	25.0 (7.96)	25.2 (9.94)	198 (64.8)
  	Ivacaftor	0.602 (0.304)	9.34 (3.81)	3.66 (2.25)

  Absorption

  When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

  Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) t_maxof lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.

  Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) t_maxof ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.

  Distribution

  Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.

  Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.

  Elimination

  The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.

  Metabolism

  Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces.

  In vitro

  and

  in vivo

  data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation.

  Ivacaftor is extensively metabolized in humans.

  In vitro

  and

  in vivo

  data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans.

  Excretion

  Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent).

  Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

  Specific Populations

  Pediatric Patients

  The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses:

  Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group

  Age Group	Weight	Dose	Mean Lumacaftor (SD)The mean lumacaftor (SD) AUCssis comparable to the mean AUCssin patients aged 12 years and older administered ORKAMBI tablets. AUCss(µg∙h/mL)	Mean Ivacaftor (SD)The mean ivacaftor (SD) AUCssis comparable to the mean AUCssin patients aged 12 years and older administered ORKAMBI tablets. AUCss(µg∙h/mL)
  Patients aged 1 to <2 years	7 kg to <9 kg	lumacaftor 75 mg/ivacaftor 94 mg every 12 hours.	234	7.98
  	9 kg to <14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	191 (40.6)	5.35 (1.61)
  	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	116	5.82
  Patients aged 2 through 5 years	<14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	180 (45.5)	5.92 (4.61)
  	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	217 (48.6)	5.90 (1.93)
  Patients aged 6 through 11 years	-	lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.	203 (57.4)	5.26 (3.08)
  Patients aged 12 to <18 years	-	lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.	241 (61.4)	3.90 (1.56)

  Male and Female Patients

  The pharmacokinetics of ORKAMBI was evaluated using a population PK analyses of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females.

  Patients with Renal Impairment

  Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment

  [see

  Use in Specific Populations (8.7)

  ]

  .

  Patients with Hepatic Impairment

  Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC_0-12h) and approximately 30% higher C_maxfor both lumacaftor and ivacaftor compared with healthy subjects matched for demographics.

  Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI

  [see

  Dosage and Administration (2.2)

  ,

  Warnings and Precautions (5.1)

  ,

  Adverse Reactions (6)

  , and

  Use in Specific Populations (8.6)

  ]

  .

  Drug Interaction Studies

  Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies

  [see

  Drug Interactions (7)

  ]

  .

  Potential for Lumacaftor/Ivacaftor to Affect Other Drugs

  Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction

  [see

  Drug Interactions (7.3)

  ]

  .

  Based on

  in vitro

  results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates

  [see

  Drug Interactions (7.5)

  ]

  .

  In vitro

  studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed

  in vitro

  .

  In vitro

  studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates

  [see

  Drug Interactions (7.4)

  ]

  .

  Potential for Other Drugs to Affect Lumacaftor/Ivacaftor

  Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors

  [see

  Dosage and Administration (2.3)

  ,

  Warnings and Precautions (5.7)

  , and

  Drug Interactions (7)

  ]

  .

  The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 6

  [see

  Dosage and Administration (2.3)

  ,

  Warnings and Precautions (5.7)

  , and

  Drug Interactions (7)

  ]

  .

  Table 6: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h

  Co-administered Drug	Dose of Co-administered Drug	Effect on PK↑ = increase, ↓ = decrease, ↔ = no change.	Mean Ratio (90% CI) of Lumacaftor and Ivacaftor No Effect=1.0
  			AUC	Cmax
  CI = Confidence Interval; PK = Pharmacokinetics.
  CYP3A inhibitor: itraconazole	200 mg once daily	↔ Lumacaftor	0.97 (0.91, 1.02)	0.99 (0.92, 1.05)
  		↑ Ivacaftor	4.30The net exposure of ivacaftor 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. (3.78, 4.88)	3.64 (3.19, 4.17)
  CYP3A inducer: rifampin	600 mg once daily	↔ Lumacaftor	0.87 (0.81, 0.93)	0.96 (0.87, 1.05)
  		↓ Ivacaftor	0.43 (0.38, 0.49)	0.50 (0.43, 0.58)
  Other: ciprofloxacin	750 mg q12h	↔ Lumacaftor	0.86 (0.79, 0.95)	0.88 (0.80, 0.97)
  		↔ Ivacaftor	1.29 (1.12, 1.48)	1.29 (1.11, 1.49)
  )
• When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dosage for the first week of treatment. (
  2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors

  No dosage adjustment is necessary when CYP3A inhibitors are initiated in patients already taking ORKAMBI. However, when initiating ORKAMBI in patients currently taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment based on age as follows

  [see

  Dosage and Administration (2.1)

  and

  Drug Interactions (7.1)

  ]:

  • 1 through 5 years of age: 1 packet of granules every other day
  • 6 years of age and older: 1 tablet daily

  Following this one-week period, resume the recommended daily dosage.

  If ORKAMBI is interrupted for more than one-week and then re-initiated while taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment re-initiation based on age as follows:

  • 1 through 5 years of age: 1 packet of granules every other day
  • 6 years of age and older: 1 tablet daily

  Following this one-week period, resume the recommended daily dosage.
  ,
  7.1 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 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). Therefore, no dosage adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI. However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dosage as recommended for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose

  [see

  Dosage and Administration (2.3)

  ]

  .

  Examples of strong CYP3A inhibitors include:

  • ketoconazole, itraconazole, posaconazole, and voriconazole.
  • telithromycin, clarithromycin.

  No dosage adjustment is recommended when used with moderate or weak CYP3A inhibitors.
  ,
  12.3 Pharmacokinetics

  The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor.

  Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF

  	Drug	Cmax (μg/mL)	t½Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects. (h)	AUC0-12h (μg∙h/mL)
  Lumacaftor 400 mg q12h/ Ivacaftor 250 mg q12h	Lumacaftor	25.0 (7.96)	25.2 (9.94)	198 (64.8)
  	Ivacaftor	0.602 (0.304)	9.34 (3.81)	3.66 (2.25)

  Absorption

  When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

  Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) t_maxof lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.

  Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) t_maxof ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.

  Distribution

  Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.

  Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.

  Elimination

  The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.

  Metabolism

  Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces.

  In vitro

  and

  in vivo

  data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation.

  Ivacaftor is extensively metabolized in humans.

  In vitro

  and

  in vivo

  data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans.

  Excretion

  Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent).

  Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

  Specific Populations

  Pediatric Patients

  The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses:

  Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group

  Age Group	Weight	Dose	Mean Lumacaftor (SD)The mean lumacaftor (SD) AUCssis comparable to the mean AUCssin patients aged 12 years and older administered ORKAMBI tablets. AUCss(µg∙h/mL)	Mean Ivacaftor (SD)The mean ivacaftor (SD) AUCssis comparable to the mean AUCssin patients aged 12 years and older administered ORKAMBI tablets. AUCss(µg∙h/mL)
  Patients aged 1 to <2 years	7 kg to <9 kg	lumacaftor 75 mg/ivacaftor 94 mg every 12 hours.	234	7.98
  	9 kg to <14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	191 (40.6)	5.35 (1.61)
  	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	116	5.82
  Patients aged 2 through 5 years	<14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	180 (45.5)	5.92 (4.61)
  	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	217 (48.6)	5.90 (1.93)
  Patients aged 6 through 11 years	-	lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.	203 (57.4)	5.26 (3.08)
  Patients aged 12 to <18 years	-	lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.	241 (61.4)	3.90 (1.56)

  Male and Female Patients

  The pharmacokinetics of ORKAMBI was evaluated using a population PK analyses of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females.

  Patients with Renal Impairment

  Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment

  [see

  Use in Specific Populations (8.7)

  ]

  .

  Patients with Hepatic Impairment

  Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC_0-12h) and approximately 30% higher C_maxfor both lumacaftor and ivacaftor compared with healthy subjects matched for demographics.

  Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI

  [see

  Dosage and Administration (2.2)

  ,

  Warnings and Precautions (5.1)

  ,

  Adverse Reactions (6)

  , and

  Use in Specific Populations (8.6)

  ]

  .

  Drug Interaction Studies

  Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies

  [see

  Drug Interactions (7)

  ]

  .

  Potential for Lumacaftor/Ivacaftor to Affect Other Drugs

  Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction

  [see

  Drug Interactions (7.3)

  ]

  .

  Based on

  in vitro

  results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates

  [see

  Drug Interactions (7.5)

  ]

  .

  In vitro

  studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed

  in vitro

  .

  In vitro

  studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates

  [see

  Drug Interactions (7.4)

  ]

  .

  Potential for Other Drugs to Affect Lumacaftor/Ivacaftor

  Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors

  [see

  Dosage and Administration (2.3)

  ,

  Warnings and Precautions (5.7)

  , and

  Drug Interactions (7)

  ]

  .

  The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 6

  [see

  Dosage and Administration (2.3)

  ,

  Warnings and Precautions (5.7)

  , and

  Drug Interactions (7)

  ]

  .

  Table 6: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h

  Co-administered Drug	Dose of Co-administered Drug	Effect on PK↑ = increase, ↓ = decrease, ↔ = no change.	Mean Ratio (90% CI) of Lumacaftor and Ivacaftor No Effect=1.0
  			AUC	Cmax
  CI = Confidence Interval; PK = Pharmacokinetics.
  CYP3A inhibitor: itraconazole	200 mg once daily	↔ Lumacaftor	0.97 (0.91, 1.02)	0.99 (0.92, 1.05)
  		↑ Ivacaftor	4.30The net exposure of ivacaftor 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. (3.78, 4.88)	3.64 (3.19, 4.17)
  CYP3A inducer: rifampin	600 mg once daily	↔ Lumacaftor	0.87 (0.81, 0.93)	0.96 (0.87, 1.05)
  		↓ Ivacaftor	0.43 (0.38, 0.49)	0.50 (0.43, 0.58)
  Other: ciprofloxacin	750 mg q12h	↔ Lumacaftor	0.86 (0.79, 0.95)	0.88 (0.80, 0.97)
  		↔ Ivacaftor	1.29 (1.12, 1.48)	1.29 (1.11, 1.49)
  )

• Tablets: 100 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters "1V125" in black ink on one side and plain on the other.
• Tablets: 200 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters "2V125" in black ink on one side and plain on the other.
• Oral granules: Unit-dose packets containing lumacaftor 75 mg/ivacaftor 94 mg or lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet; supplied as small, white to off-white granules in unit-dose packets.

There are limited and incomplete human data from clinical trials and postmarketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 7 (rats) and 45 (rabbits) times the exposure at the MRHD. No adverse developmental effects were observed after oral administration of either lumacaftor or ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.