Lumacaftor and ivacaftor

What is Lumacaftor and ivacaftor?

• Lumacaftor chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid; Molecular formula: C24H18F2N2O5; Molecular weight: 452.41; It is a white to off-white powder that is practically insoluble in water (0.02 mg/mL).
• Ivacaftor chemical name: N-(2,4-diert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide; Molecular formula: C24H28N2O3; Molecular weight: 392.49; It is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL).

Ivacaftor and lumacaftor

What are the uses of this medicine?

It is indicated for the treatment of cystic fibrosis (CF) in patients age 2 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.

How does this medicine work?

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

Who Should Not Use this medicine?

The efficacy and safety of this drug have not been established in patients with CF other than those homozygous for the F508del mutation.

What are the brand names and dosage forms of this medicine?

• Brand name: Orkambi
• Dosage forms:

1. Tablets: 100 mg lumacaftor and 125 mg ivacaftor
2. Tablets: 200 mg lumacaftor and 125 mg ivacaftor
3. Oral granules: Unit-dose packets containing lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet

Is this medicine FDA approved?

It is approved by US FDA on Sep 28, 2016 for Use in Children with Cystic Fibrosis Ages 6 through 11 who have Two Copies of the F508del Mutation.

What are the active and inactive ingredients in this medicine?

• Active ingredients:

1. Lumacaftor
2. Ivacaftor

• Inactive ingredients

1. Microcrystalline cellulose
2. Croscarmellose sodium
3. Hypromellose acetate succinate 06081224 (3 MM2/S)
4. Magnesium stearate
5. Povidone, unspecified
6. Sodium lauryl sulfate
7. Carminic acid
8. FD&C Blue no. 1
9. FD&C Blue no. 2
10. Polyethylene glycol 3350
11. Polyvinyl alcohol, unspecified
12. Talc
13. Titanium dioxide
14. Ammonia
15. Ferrosoferric oxide
16. Propylene glycol
17. Shellac

How should this medicine be used?

• Take ORKAMBI exactly as your doctor tells you to take it.
• Always take ORKAMBI tablets or granules with foods that contain fat. Examples of fat containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt).
• Take your doses of ORKAMBI 12 hours apart.
• If you miss a dose within 6 hours of when you usually take it, take your dose with fat-containing food as soon as possible.
• If you miss a dose and it is more than 6 hours after the time you usually take it, skip that dose only and take the next dose when you usually take it. Do not take 2 doses at the same time to make up for your missed dose.
• Tell your doctor if you stop ORKAMBI for more than 1 week. Your doctor may need to change your dose of ORKAMBI or other medicines you take.

ORKAMBI Tablets (ages 6 years and older):

• Each ORKAMBI box contains 4 weekly cartons.
• Each carton contains 7 daily blister strips.
• Each blister strip contains 4 tablets so you can take 2 tablets for the morning and 2 tablets for the evening.
• You may cut along the dotted line to separate your morning dose from your evening dose.
• To take your morning dose, unpeel the paper backing from a blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food.
• 12 hours after your previous dose, open another blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food.

ORKAMBI Oral Granules (ages 2 to under 6 years old):

• Hold the packet with the cut line on top.
• Shake the packet gently to settle the ORKAMBI granules.
• Tear or cut packet open along cut line.
• Carefully pour all of the ORKAMBI granules in the packet into 1 teaspoon (5 mL) of soft food or liquid in a small container (like an empty bowl).

1. The food or liquid should be at or below room temperature.
2. Examples of soft foods or liquids include puréed fruits, flavored yogurt or pudding, and milk or juice.

• Mix the ORKAMBI granules with food or liquid.
• After mixing, give ORKAMBI within 1 hour. Make sure all medicine is taken.
• Give a child fat-containing food just before or just after the ORKAMBI granules dose.

What special precautions should I follow?

Talk to your doctor before taking ORKAMBI if you take any of the following medicines or supplements:

• Inhibitors of CYP3A; Examples: ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin.
• Inducers of CYP3A; Examples: rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort (Hypericum perforatum).
• CYP3A Substrates; Examples: Benzodiazepines such as midazolam, triazolam, Immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI).
• CYP2B6 and CYP2C Substrates
• Digoxin and Other P-gp Substrates
• Anti-allergics and Systemic Corticosteroids
• Antibiotics: clarithromycin, erythromycin, and telithromycin.
• Antifungals
• Anti-inflammatories
• Antidepressants
• Hormonal Contraceptives
• Oral Hypoglycemics
• Proton Pump Inhibitors, H2 Blockers, Antacids
• Warfarin

What side effects can this medication cause?

• Worsening of liver function
• High liver enzymes in the blood
• Breathing problems
• An increase in blood pressure
• Abnormality of the eye lens (cataract)
• Most common side effects are:

1. nausea
2. diarrhea
3. fatigue
4. increase in a certain blood enzyme called creatine phosphokinase
5. rash
6. gas
7. common cold, including sore throat, stuffy or runny nose
8. flu or flu-like symptoms
9. irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual bleeding

What to do in case of emergency/overdose?

• 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.
• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.

Can this medicine be used in pregnancy?

There are limited and incomplete human data from clinical trials and post-marketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk.

Can this medicine be used in children?

Long-term use of Orkambi (lumacaftor/ivacaftor), an approved cystic fibrosis (CF) treatment, is safe and effective for children between ages 2 and 5 with two copies of the disease-causing F508del mutation in the CFTR gene, a study reported.

What should I know about storage and disposal of this medication?

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) .

• Dailymed label info on Lumacaftor and ivacaftor
• FDA Lumacaftor and ivacaftor

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