Orkambi

Last updated on RxList: 11/16/2020
Orkambi Side Effects Center

What Is Orkambi?

Orkambi (lumacaftor/ivacaftor) is a combination of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.

What Are Side Effects of Orkambi?

Common side effects of Orkambi include:

  • shortness of breath,
  • sore throat and stuffy nose (nasopharyngitis),
  • nausea,
  • diarrhea,
  • upper respiratory tract infection,
  • fatigue,
  • abnormal breathing,
  • increased blood creatine phosphokinase,
  • rash,
  • gas,
  • runny nose,
  • flu symptoms,
  • menstrual changes, and
  • increases in blood pressure.

Dosage for Orkambi

The dose of Orkambi for adults and pediatric patients age 12 years and older is two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours.

What Drugs, Substances, or Supplements Interact with Orkambi?

Orkambi may interact with antifungals, antibiotics, rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort, benzodiazepines, immunosuppressants, digoxin, corticosteroids, ibuprofen, antidepressants, hormonal contraceptives, oral hypoglycemics, proton pump inhibitors (PPIs), H2 blockers, antacids, and warfarin. Tell your doctor all medications and supplements you use.

Orkambi During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Orkambi. Orkambi may decrease the effectiveness of hormonal contraceptives. Discuss effective contraception alternatives with your doctor. Orkambi may pass into breast milk and its effects on a nursing infant are unknown. Consult your doctor before breastfeeding.

Additional Information

Our Orkambi (lumacaftor/ivacaftor) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Orkambi Consumer Information

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Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • shortness of breath, tightness in your chest; or
  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • breathing problems;
  • feeling tired;
  • nausea, gas, diarrhea;
  • rash;
  • flu symptoms;
  • changes in your menstrual periods; or
  • cold symptoms such as runny or stuffy nose, sinus pain, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Orkambi (Lumacaftor and Ivacaftor Film-coated Tablets for Oral Administration)

Orkambi Professional Information

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the label:

  • Use in Patients with Advanced Liver Disease [see WARNINGS AND PRECAUTIONS]
  • Liver-related Events [see WARNINGS AND PRECAUTIONS]
  • Respiratory Events [see WARNINGS AND PRECAUTIONS]
  • Effect on Blood Pressure [see WARNINGS AND PRECAUTIONS]

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 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 2 double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2).

In addition, the following clinical trials have been conducted:

  • A 24-week open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation.
  • A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation.
  • A 24-week, open label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV1 <40).
  • A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation.

Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 received placebo.

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 ages 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.

Table 3: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Ages 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration

Adverse Reaction (Preferred Term) ORKAMBI
N=369 (%)
Placebo
N=370 (%)
Dyspnea 48 (13) 29 (8)
Nasopharyngitis 48 (13) 40(11)
Nausea 46(13) 28 (8)
Diarrhea 45(12) 31 (8)
Upper respiratory tract infection 37 (10) 20 (5)
Fatigue 34 (9) 29 (8)
Respiration abnormal 32 (9) 22 (6)
Blood creatine phosphokinase increased 27 (7) 20 (5)
Rash 25 (7) 7 (2)
Flatulence 24 (7) 11 (3)
Rhinorrhea 21 (6) 15 (4)
Influenza 19 (5) 8 (2)

The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter Phase 3 safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, Phase 3 clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2. Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%).

In a 24-week, open-label, multicenter Phase 3 study in 60 patients aged 2 through 5 years with CF who are 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 x ULN elevations was similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 x ULN) associated with bilirubin elevation >2 x ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 x ULN.

Among 6 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 5 days of the start of dosing and resolved following discontinuation of ORKAMBI [see WARNINGS AND PRECAUTIONS].

During the 24-week, open-label Phase 3 clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5%, 9%, and 19%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24 week, placebo-controlled Phase 3 clinical trial in 204 patients aged 6 through 11 years (Trial 4), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1%, 5%, and 13% in the lumacaftor/ivacaftor patients, and 2%, 3%, and 8% in the placebo treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

During the 24-week, open-label Phase 3 clinical study in 60 patients aged 2 through 5 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels > 2 x ULN. Three patients 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 FEV1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see WARNINGS AND PRECAUTIONS].

Duringa 24-week, open label, Phase 3b clinicaltrialin 46 patients aged 12 yearsand older (Trial 5) with advanced lungdisease(ppFEV1<40) [mean ppFEV129.1at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65% [see WARNINGS AND PRECAUTIONS].

During the 24-week, open-label Phase 3 clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58).

During the 24 week, placebo-controlled Phase 3 clinical trial (Trial 4) in patients aged 6 through 11 years (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]), the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. 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%) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

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 [see WARNINGS AND PRECAUTIONS].

Post-marketing Experience

Because post-marketing 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.

Post-marketing cases of liver function decompensation including liver failure leading to death have been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with ORKAMBI [see WARNINGS AND PRECAUTIONS].

Read the entire FDA prescribing information for Orkambi (Lumacaftor and Ivacaftor Film-coated Tablets for Oral Administration)

© Orkambi Patient Information is supplied by Cerner Multum, Inc. and Orkambi Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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