Lumacaftor/ Ivacaftor- Orkambi- @-( July 2015)- Respiratory
Drug Name:Lumacaftor/ Ivacaftor- Orkambi- @-( July 2015)- Respiratory
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
• Drug interactions:
Use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions.
Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended.
• Cataracts:
Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI.
Indication:
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ORKAMBI safely and effectively. See full prescribing information for ORKAMBI.
ORKAMBI™ (lumacaftor/ivacaftor) tablets, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE-
ORKAMBI is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, 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. 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. (
Limitations of Use: The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
HIGHLIGHTS OF PRESCRIBING INFORMATION
• Liver-related events: Elevated transaminases (ALT/AST) have been These highlights do not include all the information needed to use observed in some cases associated with elevated bilirubin. Measure ORKAMBI safely and effectively.
See full prescribing information for serum transaminases and bilirubin before initiating ORKAMBI, every ORKAMBI. 3 months during the first year of treatment, and annually thereafter.
For patients with a history of ALT, AST, or bilirubin elevations, more ORKAMBI® (lumacaftor/ivacaftor) tablets, for oral use frequent monitoring should be considered. Interrupt dosing in patients
Initial U.S. Approval: 2015
NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL
PRODUCTS APPROVED FOR 2015
Certain drugs are classified as New molecular Emtities- NME- for FDA review
Many of these products contain active moieties that have not been approved
by FDA previously, either as a single ingredient or as part of a combination
products; these products frequently provide important new therapies for the
patients.
Some drugs are characterized as NMEs for administrative purposes ,but
nonetheless contain certain active moieties in products that have been
previously approved by FDA. For example, CDER classifies biological
products submitted in an application under section 351(a) of the Public
Service Act as NME for purposes of FDA review, regardless of whether
the agency previously approved a related active moiety in a different
product.
FDAs classification of a drug as an -NME- for review purposes is distinct
from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-
within the meaning of the Federal Food,Drug, and Cosmetic Act
No.15
Drug Name - Lumacaftor 200mg/Ivacaftor 125mg
Active Ingredient- Orkambi
Date of approval - 7/02/2015
FDA-approved use - To treat cystic fibrosis
Approved by US FDA on 7/02/2015- (Ref- FDA approved List- 2015)
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions to ORKAMBI (occurring in =5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza.
Contra-Indications:
CONTRAINDICATIONS
• None.
WARNINGS AND PRECAUTIONS
• Use in patients with advanced liver disease: ORKAMBI should be used with caution in these patients and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced.
• Liver-related events:
Elevated transaminases (ALT/AST) have been observed in some cases associated with elevated bilirubin.
Measure serum months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Interrupt dosing in patients with ALT or AST >5 x upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x ULN. Following resolution, consider the benefits and risks of resuming dosing.
• Respiratory events:
Chest discomfort, dyspnea, and respiration abnormal were observed more commonly during initiation of ORKAMBI. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy.
• Drug interactions:
Use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions.
Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended.
• Cataracts:
Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI. (5.5)
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
ORKAMBI is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, 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. 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.
Limitations of Use: The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
DOSAGE AND ADMINISTRATION
• Adults and pediatric patients age 12 years and older: two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours.
• Reduce dose in patients with moderate or severe hepatic impairment.
• When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dose for the first week of treatment.
DOSAGE FORMS AND STRENGTHS
• Tablets: lumacaftor 200 mg and ivacaftor 125 mg.
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advanced Liver Disease-
Inform patients that worsening of liver function in patients with advanced liver disease occurred in some patients treated with ORKAMBI. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced
Abnormalities in Liver Function and Testing-
Inform patients that abnormalities in liver function have occurred in patients treated with ORKAMBI. Blood tests to measure transaminases (ALT and AST) and bilirubin will be performed prior to initiating ORKAMBI, every 3 months during the first year of therapy, and annually thereafter
Respiratory Events -
Inform patients that chest discomfort, dyspnea, and respiration abnormal were more common during initiation of ORKAMBI therapy. Additional monitoring of patients with ppFEV1 <40 is recommended during initiation of therapy
Drug Interactions with CYP3A Inhibitors and Inducers-
Ask patients to tell you all the medications they are taking, including any herbal supplements or vitamins. Co–administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
Instruct patients on alternative methods of birth control because hormonal contraceptives should not be relied upon as an effective method of contraception and there is an increased incidence of menstruation-related adverse reactions when co-administered with ORKAMBI
When initiating ORKAMBI in patients taking strong CYP3A inhibitors (e.g., itraconazole),-
instruct the patient to reduce the dose of ORKAMBI to 1 tablet daily for the first week of treatment. Following this period, continue with the recommended daily dose
Patients should be instructed to tell their doctor if they stop ORKAMBI for more than 1 week while they are also taking a strong CYP3A inhibitor because the dose of ORKAMBI would need to be reduced upon re-initiation.
The dose of ORKAMBI should be reduced to 1 tablet daily for the first week upon treatment re-initiation. Following this period, continue with the recommended daily dose [
Use in Patients with Hepatic Impairment-
Inform patients with moderate hepatic impairment (Child-Pugh Class B) to reduce the dose of ORKAMBI to 2 tablets in the morning and 1 tablet in the evening.
If initiating ORKAMBI in a patient with severe hepatic impairment,
after weighing the risks and benefits of treatment, instruct the patient to take a maximum dose of 1 tablet (lumacaftor 200 mg/ivacaftor 125 mg) every 12 hours, or less
Administration -
Inform patients that ORKAMBI is best absorbed by the body when taken with fat-containing food. A typical CF diet will satisfy this requirement.
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), etc.
Inform patients that if a dose is missed and they remember the missed dose within 6 hours, the patients should take the dose with fat-containing food.
If more than 6 hours elapsed after the usual dosing time, the patients should skip that dose and resume the normal schedule for the following dose.
Patients should be informed not to take a double dose make up for the forgotten dose
Cataracts -
Inform patients that abnormalities of the eye lens (cataract) have been noted in some children and adolescents receiving ivacaftor, a component of ORKAMBI. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ORKAMBI treatment
Manufactured for Vertex Pharmaceuticals Incorporated Boston, MA 02210
VERTEX, and the VERTEX triangle logo are registered trademarks and ORKAMBI is a trademark of Vertex Pharmaceuticals Incorporated.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
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.
2.Pharmacokinetics
The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF.
After twice-daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor.
The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor.
Absorption
When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.
Distribution
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin.
After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.
Elimination
The half-life of lumacaftor is approximately 26 hours in patients with CF.
The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 238 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.
Metabolism
Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation.
Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans.
Excretion
Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent).
Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).
Specific Populations-
Age Pediatric Population
The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses
Pediatric patients 12 to less than 18 years of age
Following oral administration of ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, the mean lumacaftor (±SD) AUCss was 253 (68.6) µg/mL*h and is similar to the mean AUCss in adult patients administered ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.
The mean ivacaftor (±SD) AUCss was 3.84 (1.54) µg/mL*h and is similar to the mean AUCss in adult patients administered ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours [see Use in Specific Populations (8.4)].
Sex
The pharmacokinetics of ORKAMBI was evaluated using a population PK analysis of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females.
Renal Impairment
Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment
Hepatic Impairment
Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC0-12h) and approximately 30% higher Cmax for both lumacaftor and ivacaftor compared with healthy subjects matched for demographics.
Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI
Drug Interaction Studies
Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies
Potential for Lumacaftor/Ivacaftor to Affect Other Drugs
Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy.
The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction
Based on in vitro results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp.
Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates [see Drug Interactions (7.5)].
In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. In vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates
Potential for Other Drugs to Affect Lumacaftor/Ivacaftor
Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Teratogenic effects: Pregnancy Category B.
There are no adequate and well-controlled trials of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women.
Embryofetal development studies in rats and rabbits were conducted with the individual components of ORKAMBI, lumacaftor and ivacaftor.
Because animal reproduction studies are not always predictive of human response, ORKAMBI should be used during pregnancy only if clearly needed.
2. Nursing Mothers
Both lumacaftor and ivacaftor are excreted into the milk of lactating female rats. Excretion of lumacaftor or ivacaftor into human milk is probable.
There are no human studies that have investigated the effects of lumacaftor and ivacaftor on breast-fed infants. Caution should be exercised when ORKAMBI is administered to a nursing woman.
3. Pediatric Use
The safety and efficacy of ORKAMBI in patients with CF younger than age 12 years have not been established.
4. Geriatric Use
CF is largely a disease of children and young adults. Clinical trials of ORKAMBI did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.
5.Hepatic Impairment
No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening (lumacaftor 600 mg/ivacaftor 375 mg total daily dose) is recommended for patients with moderate hepatic impairment (Child-Pugh Class B).
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment.
Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (lumacaftor 400 mg/ivacaftor 250 mg total daily dose), or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment
6.Renal Impairment
ORKAMBI has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease.
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.
OVERDOSAGE
There have been no reports of overdose with ORKAMBI.
The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs).
Adverse events reported at an increased incidence of =5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%).
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.
