Ivacaftor

Ivacaftor belongs to the pharmacological class of Cystic Fibrosis Transmembrane Conductance Regulator Potentiator. Ivacaftor has been approved for relieving symptoms and for treating and maintaining episodes of Cystic Fibrosis

Ivacaftor is found to be well absorbed in the gastrointestinal tract. The mean volume of distribution of the ivacaftor in the fed condition was found to be 122L. Ivacaftor is found to be extensively metabolized in humans. The in vitro and clinical studies indicate that ivacaftor reports CYP3A primarily metabolizes Ivacaftor. From this metabolism, the major formed metabolites are found to be M1 and M6. M1 is considered pharmacologically active. After oral administration, it is found that Ivacaftor is found to be mainly eliminated in the form of feces after metabolic conversion, and this elimination represents a 87.8% of the dose of Ivacaftor.

The common side effects associated with Ivacaftor are fever, headache, diarrhea, dizziness, flu symptoms, cold, and sore throat.

Ivacaftor is found to be available in the form of Oral granules and oral tablets. Ivacaftor is available in the U.S., Canada, E.U., India, Australia, and Japan.

Ivacaftor belongs to the pharmacological class of Cystic Fibrosis Transmembrane Conductance Regulator Potentiator. Ivacaftor has been approved for relieving symptoms as well as for the treatment and maintenance of episodes of Cystic Fibrosis

Ivacaftor is said to be a potentiator of the Cystic Fibrosis Transmembrane protein. The Cystic Fibrosis Transmembrane protein is a chloride channel at the surface of the epithelial cells in the multiple organs. Ivacaftor is found to facilitate an increased chloride transport by potentiating the channel opening probability (or gating) of Cystic Fibrosis Transmembrane protein located at the cell surface. The overall level of ivacaftor-mediated Cystic Fibrosis Transmembrane chloride transport is dependent on the amount of Cystic Fibrosis Transmembrane protein at the cell surface and how responsive a particular mutant Cystic Fibrosis Transmembrane protein is to ivacaftor potentiation.

Ivacaftor had been approved for relieving symptoms as well as for the treatment and maintenance of episodes of Cystic Fibrosis

After the administration with the fat-containing food, the peak plasma concentrations of Ivacaftor were reached at four hours Tmax with a maximum concentration Cmax of 768 ng/mL.

Ivacaftor is available in oral granules and oral tablets.

Ivacaftor can be used in the treatment of the following conditions:

• Cystic fibrosis

Ivacaftor can help to relieve symptoms and also for the treatment and maintenance of cystic fibrosis.

Ivacaftor is approved for use in the following clinical indications/conditions:

• Cystic fibrosis

Oral granules and tablets are to be taken orally with water.

Oral granules

25mg, 50mg, 75mg

Oral tablet

150mg

Oral granules and Oral tablets.

• Dosage Adjustments in Pediatric Patients:

Oral:

Infants 4 to <6 months weighing ≥5 kg: Oral granules: 25 mg granule packet every 12 hours.

Infants ≥6 months and Children <6 years: Oral granules:

5 to <7 kg: 25 mg granule packet every 12 hours.

7 to <14 kg: 50 mg granule packet every 12 hours.

≥14 kg: 75 mg granule packet every 12 hours.

Children ≥6 years and Adolescents: Oral tablet: 150 mg every 12 hours.

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol intake should be avoided in patients, especially those with an underlying liver disorder or liver dysfunction.

A diet containing food with high sugar content and carbohydrates should be restricted. This includes jams, candies, chips, pies, cakes, honey, cookies,and bread. It is also advised to limit or reduce the intake of cholesterol as well as saturated fat and instead choose poultry, lean meat, or fish.

The dietary restrictions should be individualized as per the patient's requirements.

There are found to be no contraindications regarding the use of ivacaftor.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

Transaminase (ALT or AST) Elevations

Elevated transaminases had been reported in patients with Cystic Fibrosis who were receiving Ivacaftor. Hence it is recommended that ALT and AST should be assessed prior to initiating Ivacaftor, every three months during the first year of treatment, and annually after that. For the patients with a history of transaminase elevations,frequent monitoring of liver function tests should be considered. Patients who develop an increased transaminase levels should be closely monitored until the abnormalities resolve.

Dosing should be interrupted in patients having ALT or AST of greater than five times the upper limit of normal (ULN). Following the resolution of transaminase elevations, consider the benefits and risks of resuming Ivacaftor dosing.

Concomitant Use with CYP3A Inducers

The use of Ivacaftor with strong CYP3A enzyme inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which might reduce the therapeutic effectiveness of Ivacaftor. Therefore, co-administration of Ivacaftor with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended.

Cataracts

Cases of the non-congenital lens opacities/cataracts had been reported in pediatric patients treated with Ivacaftor. Although other risk factors were present in some cases i.e.such as corticosteroid use and/or exposure to radiation, a possible risk attributable to Ivacaftor cannot be excluded. Baseline and the follow-up ophthalmological examinations are recommended in pediatric patients initiating Ivacaftor treatment.

Avoid alcohol usage while on Ivacaftor medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

There is found to be no information regarding the presence of ivacaftor in the human milk and the effects on the breastfed infant, or the effects on the milk production. Ivacaftor is found to be excreted into the milk of lactating rats. Due to species-specific differences in lactation physiology, animal lactation data might not reliably predict levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ivacaftor and any potential adverse effects on the breastfed child from Ivacaftor or from the underlying maternal condition.

Pregnancy Category B

There is limited and incomplete human data from clinical trials and postmarketing reports on the use of Ivacaftor in pregnant women. In animal reproduction studies, the oral administration of ivacaftor to the pregnant rats and rabbits during organogenesis had demonstrated no teratogenicity or adverse effects on the fetal development at doses that produced maternal exposures up to approximately 5 in rats and 11 in rabbits times the exposure at MRHD. No adverse developmental effects had been observed after oral administration of ivacaftor to pregnant rats from organogenesis through the lactation at doses that produced maternal exposures approximately three times the exposures at the MRHD, respectively.

The background risk of major birth defects as well as miscarriage for the indicated population is found to be unknown. In the US general population, the estimated background risk of the major birth defects is about 2% to 4%, and miscarriage is about 15% to 20% in clinically recognized pregnancies.

The food items such as Grapefruit juice or any food that contains grapefruit or Seville oranges during treatment with ivacaftor.

The adverse reactions related to Ivacaftor can be categorized as follows:

More common

• Runny or stuffy nose
• Body aches or pain
• Chest pain
• Sore throat
• Chills
• Cough
• Difficulty with breathing or trouble breathing
• Ear congestion
• Fever
• Headache
• Loss of voice
• Sneezing
• Unusual tiredness or weakness

• Loss of appetite
• Nausea
• Light-colored stools
• Vomiting
• Stomach pain
• Dark urine
• Fever with or without chills
• Yellow eyes or skin

The clinically relevant drug interactions of Ivacaftor are briefly summarized here:

Inhibitors of CYP3A

Ivacaftor is found to be a sensitive to CYP3A enzyme substrate. Co-administration with ketoconazole, a strong CYP3A enzyme inhibitor, significantly increased ivacaftor exposure which is measured as the area under the curve (AUC) by about 8.5-fold. Based on the simulations of these results, a reduction of the Ivacaftor dose is recommended when it is co-administered with strong CYP3A inhibitors, such as voriconazole, telithromycin, ketoconazole, itraconazole, posaconazole, and clarithromycin, as follows: in patients, six years and older reduce dose to one 150 mg tablet twice a week; in patients 2 to less than six years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients, 2 to less than six years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week. Co-administration with fluconazole, which is a moderate inhibitor of CYP3A, had increased ivacaftor exposure by 3-fold. Therefore, a reduction of the Ivacaftor dose is found to be recommended for the patients taking concomitant moderate CYP3A enzyme inhibitors, such as fluconazole and erythromycin, as follows: in patients six years and older, reduce the dose to one 150 mg tablet once daily; in patients 2 to less than six years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients, 2 to less than six years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily. Co-administration of Ivacaftor along with grapefruit juice, which contains one or more components that moderately inhibit CYP3A enzyme, might increase the exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with Ivacaftor.

Inducers of CYP3A

Co-administration with rifampin which is a strong CYP3A inducer, had significantly decreased ivacaftor exposure (AUC) by about 9-fold. Therefore, co-administration with the strong CYP3A inducers, such as carbamazepine, rifampin, rifabutin, phenobarbital, phenytoin, and St. John's wort, is not recommended.

Ciprofloxacin

Co-administration of Ivacaftor with ciprofloxacin had no effect on the exposure or ivacaftor. Therefore, no dose adjustment is necessary during the concomitant administration of Ivacaftor with ciprofloxacin. Potential for ivacaftor to affect other drugs

CYP3A and/or P-GP Substrates

Ivacaftor and its M1 metabolite is found to have the potential to inhibit CYP3A and P-gp. Co-administration along with oral midazolam which is a sensitive CYP3A substrate had increased midazolam exposure 1.5-fold which is consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, which is a sensitive P-gp substrate, an increased digoxin exposure by 1.3-fold with a consistent with weak inhibition of P-gp by ivacaftor. The administration of Ivacaftor might increase the systemic exposure of drugs that are the substrates of CYP3A and/or P-gp, which might increase or prolong their therapeutic effect and the adverse events. Therefore, caution and appropriate monitoring is recommended when it is co-administering Ivacaftor with sensitive CYP3A and/or P-GP substrates, such as digoxin, cyclosporine, and tacrolimus.

The common side effects of Ivacaftor include the following:

Pregnancy

Pregnancy Category B

There is limited and incomplete human data from clinical trials and postmarketing reports on the use of Ivacaftor in pregnant women. In animal reproduction studies, the oral administration of ivacaftor to the pregnant rats and rabbits during organogenesis had demonstrated no teratogenicity or adverse effects on the fetal development at doses that produced maternal exposures up to approximately 5 in rats and 11 in rabbits times the exposure at MRHD. No adverse developmental effects had been observed after oral administration of ivacaftor to pregnant rats from organogenesis through the lactation at doses that produced maternal exposures approximately three times the exposures at the MRHD, respectively.

The background risk of major birth defects and miscarriage for the indicated population is found to be unknown. In the US general population, the estimated background risk of the major birth defects is about 2% to 4%, and miscarriage is about 15% to 20% in clinically recognized pregnancies.

• Nursing Mothers

There is found to be no information regarding the presence of ivacaftor in the human milk and the effects on the breastfed infant, or the effects on the milk production. Ivacaftor is found to be excreted into the milk of lactating rats. Due to species-specific differences in lactation physiology, animal lactation data might not reliably predict levels in human milk. The developmental and health benefits of the breastfeeding should be considered along with the mother's clinical need for Ivacaftor and any potential adverse effects on the breastfed child from Ivacaftor or from the underlying maternal condition.

• Pediatric Use

The efficacy and safety of Ivacaftor in patients aged 6 to 17 years with Cystic fibrosis who had a G551S, G551D, G1244E, G1349D, G178R, S1251N, S1255P, S549N, or S549R mutation in the Cystic Fibrosis Transmembrane gene have been demonstrated.

The efficacy and safety of Ivacaftor in patients aged 6 to 17 years of age with Cystic Fibrosis who have an R117H mutation in the Cystic Fibrosis Transmembrane gene have been demonstrated. The efficacy of Ivacaftor in children 2 to less than six years of age is extrapolated from efficacy in patients six years of age ar older with support from population pharmacokinetic analyses showed a similar drug exposure levels in adults and children 2 to less than six years of age.

• Geriatric Use

Cystic Fibrosis is largely a disease of children as well as young adults. Clinical trials carried out with Ivacaftor did not include sufficient numbers of patients aged 65 years and over in order to determine whether they respond any differently from the younger patients.

Physicians should be knowledgeable and vigilant about the treatment and identification of overdosage of Ivacaftor.

There had been no reports of overdose related to Ivacaftor.

The highest single dose of Ivacaftor used in a clinical study was found to be 800 mg in a solution formulation without any further treatment-related adverse events. The highest repeated dose was found to be 450 mg in a tablet formulation every twelve hours for 4.5 days i.e.9 doses in a trial evaluating the effect of Ivacaftor on ECGs in the healthy subjects. Adverse events reported at a higher incidence had been compared to that of the placebo included dizziness as well as diarrhea.

No specific antidote is found to be available for the overdose with the Ivacaftor. Treatment of overdose with Ivacaftor consists of the general supportive measures, including monitoring of vital signs as well as the observation of the clinical status of the patient.

Pharmacodynamics

The use of Ivacaftor had been shown to both improve Cystic Fibrosis symptoms as well as modulate underlying disease pathology. This is found to be achieved by potentiating the channel opening probability (or gating) of Cystic Fibrosis Transmembrane protein in patients along with impaired gating mechanisms. This is in contrast to that of Lumacaftor, another Cystic Fibrosis medication, that functions by preventing misfolding of the Cystic Fibrosis Transmembrane protein hence thereby results in increased processing and trafficking of mature protein to the cell surface.

Pharmacokinetics

• Absorption

The exposure to ivacaftor increased approximately 2.5- to 4-fold when given food that contains fat. Therefore, Ivacaftor should be administered along with fat-containing food. Examples of fat-containing foods include cheese pizza, whole-milk dairy products, eggs, butter, peanut butter, i.e.such as whole milk, cheese, and yogurt, etc. The median (range) Tmax is found to be approximately 4.0 i.e.3.0; 6.0 hours in the fed state. Ivacaftor granules i.e.2 x 75 mg had similar bioavailability as that of the 150 mg tablet when administered with fat-containing food in adult subjects. The effect of food on ivacaftor absorption is found to be similar for Ivacaftor granules and the 150 mg tablet formulation.

• Distribution

Ivacaftor is found to be approximately 99% bound to plasma proteins, while is it primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor is found to not bind to the human red blood cells. Following the oral administration of 150 mg every 12 hours for seven days to healthy volunteers in a fed state, the mean (±SD) for the apparent volume of distribution was found to be 353 (122) L.

• Metabolism

Ivacaftor is found to be extensively metabolized in humans. In vitro and clinical studies had indicated that ivacaftor is found to be primarily metabolized by CYP3A enzyme. M1 and M6 are the two major metabolites of ivacaftor which are found in humans. M1 is said to have approximately one-sixth the potency of ivacaftor also is considered pharmacologically active. M6 has less than one-fiftieth of the potency of ivacaftor and is not considered as a pharmacologically active metabolite .

• Elimination

After the oral administration, the majority of ivacaftor i.e.87.8% is eliminated in the feces after metabolic conversion. The primary metabolites were found to be M1 and M6 which accounted for around 65% of the total dose eliminated, while 22% as M1 and 43% as M6 metabolite. There was found to be negligible urinary excretion of ivacaftor as an unchanged parent. The apparent terminal half-life was found to be approximately twelve hours followed by a single dose. The mean apparent clearance (CL/F) of ivacaftor was found to be similar for healthy subjects and patients with Cystic Fibrosis. The CL/F (Standarad deviation) for the 150 mg dose was found to be 7.3 i.e.8.4 L/hr in healthy subjects.

1. https://go.drugbank.com/drugs/DB08820
2. https://www.mayoclinic.org/drugs-supplements/ivacaftor-oral-route/side-effects/drg-20075428
3. https://www.rxlist.com/kalydeco-drug.htm
4. https://www.kalydeco.com/safety-side-effects
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203188s019lbl.pdf