Orkambi Drug Information

ORKAMBI is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Limitations of Use: The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older The recommended dosage of ORKAMBI in adults and pediatric patients aged one year and older is based on patient's age and weight as described in Table 1. Table 1: Recommended Oral Dosage of ORKAMBI in Patients Aged 1 Year and Older Instructions for ORKAMBI Oral Granules The entire content of each packet of oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice.

Food should be at room temperature or below. Each packet 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.

Administration with Fat-Containing Food for ORKAMBI Tablets and Oral Granules A fat-containing meal or snack should be consumed just before or just after dosing for all formulations. Examples of appropriate fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. Missed Dose If a patient misses a dose and remembers the missed dose within 6 hours, the patient should take the dose with fat-containing food.

If more than 6 hours elapsed after the recommended dosing time, the patient should skip that dose and resume the normal schedule for the following dose. A double dose should not be taken to make up for the forgotten dose.

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.

Table 2: Recommended Dosage for Patients with Hepatic Impairment

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: 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo.

Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients. Table 3 shows adverse reactions occurring in ≥5% of patients with CF aged 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials.

In a 24-week, open-label, multicenter, study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older. Additional information on selected adverse reactions from trials is detailed below: Description of Selected Adverse Drug Reactions Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN elevations were similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including two reported as transaminase elevations and one as hepatic encephalopathy, compared to none in the placebo group.

Of these three, one had elevated transaminases (>3 × ULN) associated with bilirubin elevation >2 × ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 × ULN. Among six patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient.

The event occurred within five days of the start of dosing and resolved following discontinuation of ORKAMBI. No patients had total bilirubin levels >2 × ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except one patient who discontinued treatment permanently.

Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations. One patient discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%).

The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV 1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment. A decline in ppFEV 1 at initiation of therapy was observed during serial post-dose spirometry assessments.

The post-dose decline was resolved by Week 16. Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%).

Increased Blood Pressure In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo. 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 3.6% and 2.2% in patients treated with ORKAMBI, respectively, compared with 1.6% and 0.5% in patients who received placebo.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ORKAMBI or drugs containing the same or similar active ingredients as ORKAMBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary: liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension.

Immune System Disorders: anaphylaxis, angioedema Nervous System Disorders: intracranial hypertension Psychiatric Disorders: anxiety, depression, suicidal ideation and behavior, insomnia

Drug Interactions Substrates of CYP3A Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended.

ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI. Strong CYP3A Inducers Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes.

Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers (e.g., rifampin, St. John's wort ) is not recommended.

Pregnancy Risk Summary 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). 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 (see Data ).

There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor. 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 respectively.

Lumacaftor did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). Maternal toxicity as evidenced by decreased body weight, decreased food consumption, and clinical signs was observed at 100 and 200 mg/kg/day without any adverse fetal effects. In a pre- and post-natal development study in pregnant female rats administered lumacaftor at 250, 500, or 1000 mg/kg/day from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day).

Placental transfer of lumacaftor was observed in pregnant rats and rabbits. Ivacaftor did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Ivacaftor did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day).

Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 15 times the MRHD). Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day).

Pediatric Use The safety and effectiveness of ORKAMBI in pediatric patients aged one year and older have been established. Use of ORKAMBI in these age groups is supported by evidence from adequate and well-controlled studies of ORKAMBI in patients aged 12 years and older with additional data as follows: Extrapolation of efficacy in patients aged 12 years and older homozygous for the F508del mutation in the CFTR gene to pediatric patients aged 1 through 11 years with support from population pharmacokinetic analyses showing similar drug exposure levels in patients aged 12 years and older and in patients aged 1 through 11 years. Trial 3 evaluated subjects with a screening ppFEV 1 ≥40.

Trial 4 evaluated subjects with a screening ppFEV 1 ≥70. The safety profile of ORKAMBI in pediatric patients 6 through 11 years of age was similar to that in patients aged 12 years and older. In Trial 3, spirometry (ppFEV 1 ) was assessed as a planned safety endpoint.

The within-group LS mean absolute change from baseline in ppFEV 1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV 1 was also assessed. The safety profile in Trial 7 was similar to that in patients aged 2 years and older.

Adverse reactions from trial 8 were generally similar to those reported in Trial 7. The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established. Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI.

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. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from post-natal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.3 to 2 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.

There have been no reports of overdose with ORKAMBI. No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.