Orkambi

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to the medication.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

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.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Orkambi has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from Orkambi, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered.

You should not use this medicine if you are allergic to ivacaftor or lumacaftor.

Some medicines can interact with ivacaftor and lumacaftor and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

• rifabutin or rifampin;

• St. John's wort;

• medicine to prevent organ transplant rejection--everolimus (Zortress), sirolimus, tacrolimus;

• a sedative--triazolam or oral midazolam; or

• seizure medicine--carbamazepine, phenobarbital, phenytoin.

To make sure ivacaftor and lumacaftor is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• high blood pressure;

• asthma or other lung disease; or

• if you have had an organ transplant.

This medicine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Use a barrier form of birth control (condom or diaphragm with spermicide). Hormonal contraception (birth control pills, injections, implants, and skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

It is not known whether ivacaftor and lumacaftor passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Ivacaftor and lumacaftor is not approved for use by anyone younger than 12 years old.

Absorption

Bioavailability

Peak plasma concentrations achieved approximately 4 hours after oral administration in the fed state.1

Steady-state concentrations achieved approximately 7 days after twice-daily oral administration.1

Lumacaftor: Systemic exposure increases with accumulation ratio of approximately 1.9.1

Ivacaftor: Steady-state exposure lower than that observed on first day of administration resulting from CYP3A induction by lumacaftor.1

Food

Administration of single dose with food containing fat resulted in systemic exposures of lumacaftor and ivacaftor approximately twofold and threefold higher, respectively, when compared with administration in fasting state.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied.1

Moderate hepatic impairment (Child-Pugh class B): AUCs and peak plasma concentrations of lumacaftor and ivacaftor increased by 50 and 30%, respectively, for both drugs when compared with healthy individuals.1

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied; magnitude of increase in systemic exposure unknown, but expected to be substantially higher than that observed in patients with moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with mild, moderate, or severe renal impairment or in those with ESRD.1 (See Renal Impairment under Cautions.)

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Lumacaftor: Approximately 99% (mainly albumin).1

Ivacaftor: Approximately 99% (mainly α1-acid glycoprotein, albumin).1

Elimination

Metabolism

Lumacaftor: Not extensively metabolized in humans; principally metabolized by oxidation and glucuronidation.1

Ivacaftor: Extensively metabolized in humans, principally by CYP3A.1 Two major metabolites are M1 and M6.1

Elimination Route

Lumacaftor: Mainly excreted unchanged in feces (51%).1 Lumacaftor and metabolites minimally excreted in urine (8.6%).1

Ivacaftor: Mainly excreted in feces (87.8%) after metabolic conversion.1 Ivacaftor and metabolites minimally excreted in urine (6.6%).1

Half-life

Lumacaftor: Approximately 26 hours in patients with cystic fibrosis.1

Ivacaftor: Approximately 9 hours in healthy individuals.1

• Lumacaftor/ivacaftor in fixed combination contains 2 drugs acting directly on CFTR protein, a chloride channel present at epithelial cell surface in multiple organs involved in salt and fluid transport.1 4 5 7 8 Lumacaftor is a CFTR corrector; ivacaftor is a CFTR potentiator.1 4 5 8

• Mutations in the gene encoding CFTR affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.4 5 7 8

• F508del mutation causes CFTR protein misfolding resulting in defective cellular processing and trafficking, which targets CFTR for degradation and reduces quantity of CFTR at cell surface.1 4 5 6 7 Small amount of F508del-CFTR reaching cell surface is less stable and has low probability of channel opening (defective gating activity).1 4 6

• Lumacaftor improves conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to cell surface.1 4 6 7

• Ivacaftor facilitates increased chloride transport by potentiating the probability of channel opening (or gating) of the CFTR protein at cell surface.1 4 6

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Take this medicine with fat-containing foods such as avocado, butter, cheese pizza, eggs, nuts, peanut butter, or whole milk dairy products (eg, whole milk, cheese, yogurt).

Tell your doctor if you stop taking this medicine for more than 1 week. Your doctor may need to change your dose of Orkambi® or other medicines you take.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For cystic fibrosis:
    • Adults and children 12 years of age and older—2 tablets every 12 hours, taken with fat-containing food. Each tablet contains 200 milligrams (mg) of lumacaftor and 125 mg of ivacaftor.
    • Children 6 to 11 years of age and older—2 tablets every 12 hours, taken with fat-containing food. Each tablet contains 100 milligrams (mg) of lumacaftor and 125 mg of ivacaftor.
    • Children younger than 6 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose, take it as soon as you can. If your next regular dose is less than 6 hours away, wait until then to use the medicine and skip the missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Use Orkambi as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine with fatty foods. This includes eggs; avocados; nuts; butter; peanut butter; cheese pizza; or whole-milk dairy products like whole milk, cheese, or yogurt.
• Keep taking Orkambi (lumacaftor and ivacaftor) as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it has been 6 hours or more since the missed dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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.

The active ingredients in Orkambi tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and ivacaftor, a CFTR potentiator, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The molecular formula for lumacaftor is C24H18F2N2O5 and for ivacaftor is C24H28N2O3. The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively. The structural formulas are:

lumacaftor

ivacaftor

Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL).

Orkambi is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each Orkambi tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

Orkambi is also available as a pink, oval-shaped, film-coated tablet for oral administration containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each Orkambi tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

Rx only

NDC 51167-809-01

Orkambi®
(Lumacaftor/Ivacaftor) tablets
200 mg/125 mg per tablet

112 tablets

Rx only

NDC 51167-700-02

Orkambi®
(Lumacaftor/Ivacaftor) tablets
100 mg/125 mg per tablet

112 tablets

Usual Adult Dose for Cystic Fibrosis:

Two tablets (ivacaftor 125 mg-lumacaftor 200 mg) orally every 12 hours with fat-containing food

Comments:
-If a dose is missed within 6 hours of the usual scheduled time, take the dose immediately with a fat-containing meal; if more than 6 hours have elapsed, skip that dose and resume the normal schedule for the following dose.

Use: For the treatment of cystic fibrosis (CF) in patients 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

Usual Pediatric Dose for Cystic Fibrosis:

6 to 11 years: Two tablets (ivacaftor 125 mg-lumacaftor 100 mg) orally every 12 hours with fat-containing food

12 years or older: Two tablets (ivacaftor 125 mg-lumacaftor 200 mg) orally every 12 hours with fat-containing food

Comments:
-If a dose is missed within 6 hours of the usual scheduled time, take the dose immediately with a fat-containing meal; if more than 6 hours have elapsed, skip that dose and resume the normal schedule for the following dose.

Use: For the treatment of CF in patients age 6 years 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.

Common side effects of Orkambi include: upper respiratory tract infection, dyspnea, chest discomfort, nausea, and skin rash. Other side effects include: influenza, and flatulence. See below for a comprehensive list of adverse effects.