Vertex Pharmaceuticals, Inc's Kalydeco

The FDA has approved Vertex Pharmaceuticals, Inc's Kalydeco (ivacaftor) tablets for the treatment of cystic fibrosis in patients who are 6 years and older.

The FDA has approved Vertex Pharmaceuticals, Inc’s Kalydeco (ivacaftor) tablets for the treatment of cystic fibrosis (CF) in patients who are 6 years and older with a G551D mutation in the CF transmembrane conductance regulator (CFTR) gene.^1,2 The approval carries the limitations that Kalydeco is not effective in patients with CF that is due to other genetic mutations, such as homozygous F508del mutation of the CFTR gene, and that Kalydeco has not been studied in other populations of patients with CF.¹

CF, a rare and life-threatening genetic disease, affects an estimated 30,000 people in the United States and 70,000 people worldwide. Although the median predicted age of survival for a patient with CF is 38 years, the median age of death is in the mid-20s. There are more than 1800 genetic mutations of the CFTR gene; approximately 4% of CF patients have the G551D mutation. The most common mutation is the F508del mutation.² By focusing on the CFTR gene, Kalydeco is the first medication available to target the cause of CF.³

Pharmacology and Pharmacokinetics

The CFTR protein is a chloride channel on the surface of epithelial cells of multiple organs. Kalydeco potentiates the CFTR protein, thus facilitating an increase in chloride transport of the G551D-CFTR protein.

Kalydeco is metabolized extensively by cytochrome P450 (CYP) 3A. Dose adjustments are required for patients with hepatic insufficiency. Kalydeco has not been studied in patients with renal insufficiency; however, no dose adjustment is required for patients with a creatinine clearance greater than 30 mL/ min. Gender does not affect the pharmacokinetics of Kalydeco.¹

Dosage and Administration

Kalydeco should be given as 150 mg every 12 hours with fat-containing food. Patients with moderate hepatic impairment should receive Kalydeco 150 mg daily. Patients with severe hepatic impairment should receive Kalydeco 150 mg daily or less frequently. Use caution in patients with a creatinine clearance less than 30 mL/min.

When coadministered with a strong CYP3A4 inhibitor, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, or clarithromycin, Kalydeco should be dosed as 150 mg twice a week. When coadministered with a moderate CYP3A4 inhibitor, such as fluconazole or erythromycin, Kalydeco should be dosed as 150 mg once a day. Consumption of grapefruit or Seville oranges should be avoided. Coadministration of Kalydeco with a strong CYP3A4 inducer, such as rifampin, rifabutin, phenobarbital, carbmazepine, phenytoin, and St. John’s Wort should also be avoided.¹

Clinical Trials

The efficacy of Kalydeco was evaluated in 2 randomized, double-blind, placebocontrolled clinical trials of 213 patients with clinically stable CF who had a G551D mutation in the CFTR gene. Trial 1 consisted of 161 patients who were 12 years and older. Trial 2 consisted of 52 patients aged 6 to 11 years. In both trials, patients were randomized in a 1:1 ratio to receive either Kalydeco or placebo in addition to their preexisting medication regimen. The primary end point of both studies was an improvement in lung function, which was determined by the change in FEV₁ at 24 weeks from baseline. Both trials showed a significant improvement in lung function in the group using Kalydeco.¹ Patients using Kalydeco also experienced fewer pulmonary exacerbations than those using placebo.²

Contraindications, Warnings, and Precautions

There are no contraindications to treatment with Kalydeco.

Transaminases (alanine transaminase [ALT] and apartate transaminase [AST]) should be evaluated before beginning treatment with Kalydeco, every 3 months during the first year of treatment, and every year thereafter. Close monitoring is required if increased transaminase levels occur. Temporarily discontinue treatment if ALT or AST is greater than 5 times the upper limit of normal. Once levels have normalized, consider the risks and benefits of treatment before restarting. Concomitant use with strong CYP3A4 inducers should be avoided.

Kalydeco is Pregnancy Category B and should only be used during pregnancy if clearly needed. There are no studies on the effect of Kalydeco on breast-fed infants; use caution in patients who are nursing. Kalydeco has not been evaluated in patients younger than 6 years.

The most common (≥8%) side effects are headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness.¹

SPT

References

1. Kalydeco complete prescribing information. Available at http://pi.vrtx.com/files/uspi_ivacaftor.pdf Accessed April 2012.

2. FDA Approves Kalydeco (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis Available at http://investors.vrtx.com/releasedetail.cfm?releaseid=644257 Accessed April 2012.

3. FDA approves Kalydeco to treat rare form of cystic fibrosis. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm Accessed April 2012.

About the Author

Monica Holmberg, PharmD, BCPS, earned her PharmD from the University of Connecticut and completed an ambulatory care residency at the Phoenix VA Healthcare System. Her practice has also included pediatrics and inpatient mental health. She resides in Phoenix, Arizona.