DRUG INTERACTIONS-

 See Full Prescribing Information for a complete list. (2.3, 7, 12.3) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch

U.S. FDA APPROVED  DRUGS DURING 2015

Sr.No-  15

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. 

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 

Drug Interactions-                                                                                                              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)

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. All other trademarks referenced herein are the property of their respective owners. ©2015 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED

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. Pharmacodynamics-                                                                                               Sweat Chloride Evaluation Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled,

Cardiac Electrophysiology-                                                                                          The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin), parallel, thorough QT study in 168 healthy subjects.

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 2 38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects.

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

Use in Specific Populations-                                                                                           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 [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.6)].

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 [see Drug Interactions (7)].

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.

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.

Because animal reproduction studies are not always predictive of human response, ORKAMBI should be used during pregnancy only if clearly needed. Lumacaftor Lumacaftor was not teratogenic in rats at approximately 8 times the maximum recommended human dose (MRHD) (on a lumacaftor AUC basis at a maternal oral dose of 2000 mg/kg/day).

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.