OFEV

Capsules contain nintedanib, a kinase inhibitor.

Nintedanib is presented as the ethanesulfonate salt (esylate), with the chemical name 1 H -Indole-6-carboxylic acid, 2,3.

• dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1).

Its structural formula is

Nintedanib esylate is a bright yellow powder with an empirical formula of C31H33N5O4ꞏC2H6O3S and a molecular weight of 649.76 g/mol.

Capsules for oral administration are available in 2 dose strengths containing 100 mg or 150 mg of nintedanib (equivalent to 120.40 mg or 180.60 mg nintedanib ethanesulfonate, respectively).

The inactive ingredients of Nintedanib Capsules are the following: Fill Material: Medium-chain triglycerides, lecithin.

Shell: gelatin, glycerin, ferric oxide red, ferric oxide yellow, titanium dioxide, black ink.

Nintedanib Capsules is a kinase inhibitor indicated in adults for: Treatment of idiopathic pulmonary fibrosis (IPF) Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype 1.1 Idiopathic Pulmonary Fibrosis Nintedanib Capsules is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF). 1.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib Capsules is indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.

Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).

Nintedanib inhibits the following

RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase-3 (FLT-3).

These kinases except for

FLT-3 have been implicated in pathogenesis of interstitial lung diseases (ILD).

Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signaling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling in ILD.

Nintedanib also inhibits the following nRTKs

Lck, Lyn and Src kinases.

The contribution of

FLT-3 and nRTK inhibition to nintedanib efficacy in ILD is unknown. 12.2 Pharmacodynamics Cardiac Electrophysiology In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval. 12.3 Pharmacokinetics The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with chronic fibrosing ILDs with a progressive phenotype, and cancer patients.

PK of nintedanib is linear.

Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range to 450 mg once daily and to 300 mg twice daily).

Accumulation upon multiple administrations in patients with IPF was 1.76-fold for AUC.

Steady-state plasma concentrations were achieved within one week of dosing.

Nintedanib trough concentrations remained stable for more than one year.

The inter-individual variability in the

PK of nintedanib was moderate to high (coefficient of variation of standard PK parameters in the range of 30% to 70%), intra-individual variability low to moderate (coefficients of variation below 40%).

Nintedanib reached maximum plasma concentrations approximately to 4 hours after oral administration as a soft gelatin capsule under fed conditions.

The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers.

Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.

After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median t max fasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.

Nintedanib follows bi-phasic disposition kinetics.

After intravenous infusion, a high volume of distribution which was larger than total body volume (V ss: 1050 L) was observed.

The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%.

Serum albumin is considered to be the major binding protein.

Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.

Elimination The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%).

Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%).

Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min. Metabolism The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202.

BIBF is subsequently glucuronidated by

UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide.

Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP3A4 being the predominant enzyme involved.

The major

CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study.

In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.

The major route of elimination of drug-related radioactivity after oral administration of [ 14 C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of nintedanib capsules was excreted as BIBF 1202.

The contribution of renal excretion to the total clearance was low (0.65% of dose).

The overall recovery was considered complete (above 90%) within 4 days after dosing.

Age, Body Weight, and Sex Based on population PK analysis, age and body weight were correlated with nintedanib exposure.

However, the effects on exposure are not sufficient to warrant a dose adjustment.

There was no influence of sex on the exposure of nintedanib.

Patients with Renal Impairment Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment.

Data in severe renal impairment (CrCl below 30 mL/min) was limited.

Patients with Hepatic Impairment A dedicated single-dose phase I pharmacokinetics study of nintedanib capsules compared 8 subjects with mild hepatic impairment (Child Pugh A) and 8 subjects with moderate hepatic impairment (Child Pugh B) to 17 subjects with normal hepatic function.

In subjects with mild hepatic impairment, the mean exposure to nintedanib was 2.4-fold higher based on Cmax (90% CI: 1.6 to 3.6) and 2.2-fold higher based on AUC 0-inf (90% CI: 1.4 to 3.5).

In subjects with moderate hepatic impairment, exposure was 6.9-fold higher based on Cmax (90% CI: 4.4 to 11.0) and 7.6-fold higher based on AUC 0-inf (90% CI: 5.1 to 11.3).

Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

Smokers In the population

PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex.

• and never-smokers.

The effect is not sufficient to warrant a dose adjustment.

Drug Interaction Studies Potential for Nintedanib to Affect Other Drugs Effect of nintedanib coadministration on pirfenidone AUC and C max was evaluated in a multiple-dose study.

Nintedanib did not have an effect on the exposure of pirfenidone.

In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2.

In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance.

Nintedanib and its metabolites, BIBF and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.

Potential for Other Drugs to Affect Nintedanib Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4.

Coadministration with the P-gp and

CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C max in a dedicated drug-drug interaction study.

In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C max upon coadministration with rifampicin compared to administration of nintedanib alone.

Effect of pirfenidone coadministration on nintedanib AUC and C max was evaluated in a multiple-dose drug-drug interaction study.

Pirfenidone did not have an effect on the exposure of nintedanib.

Concomitant treatment with nintedanib and pirfenidone was also investigated in a separate trial, which was an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks.

Similar nintedanib trough plasma concentrations were observed when comparing patients receiving nintedanib alone with patients receiving nintedanib with add-on pirfenidone.

Healthy volunteers received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state.

Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.

Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH less than 3.

However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.

In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP.

In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Elevated Liver Enzymes and Drug-Induced Liver Injury Gastrointestinal.

Disorders Embryo-Fetal Toxicity Arterial Thromboembolic Events Risk of Bleeding Gastrointestinal Perforation Nephrotic Range Proteinuria Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension.

To report SUSPECTED ADVERSE

REACTIONS, contact Edenbridge Pharmaceuticals, LLC.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of nintedanib capsules was evaluated in over 1000 IPF patients, and 332 patients with chronic fibrosing ILDs with a progressive phenotype.

Over 200 IPF patients were exposed to nintedanib capsules for more than 2 years in clinical trials.

Nintedanib capsules were studied in three randomized, double-blind, placebo-controlled, 52-week trials.

In the phase 2 (Study 1) and phase 3 (Study and Study 3) trials, 723 patients with IPF received nintedanib capsules 150 mg twice daily and 508 patients received placebo.

The median duration of exposure was 10 months for patients treated with nintedanib capsules and 11 months for patients treated with placebo.

Subjects ranged in age from to 89 years (median age of 67 years).

Most patients were male (79%) and Caucasian (60%).

The most frequent serious adverse reactions reported in patients treated with nintedanib capsules, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%).

The most common adverse events leading to death in patients treated with nintedanib capsules, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%).

In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib capsules.

• treated patients and 1.8% of placebo-treated patients.

Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib capsules-treated patients and 1% of placebo-treated patients.

The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (11%).

Adverse reactions leading to discontinuation were reported in 21% of nintedanib capsules-treated patients and 15% of placebo-treated patients.

The most frequent adverse reactions that led to discontinuation in nintedanib capsules-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).

The most common adverse reactions with an incidence of greater than or equal to 5% and more frequent in the nintedanib capsules than placebo treatment group are listed in Table 1.

In addition, hypothyroidism was reported in patients treated with nintedanib capsules, more than placebo (1.1% vs. 0.6%).

Alopecia was also reported in more patients treated with nintedanib capsules than placebo (0.8% vs. 0.4%).

Concomitant treatment with nintedanib and pirfenidone was investigated in an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks.

The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to Week 12.

Gastrointestinal adverse events were in line with the established safety profile of each component and were experienced in 37 (70%) patients treated with pirfenidone added to nintedanib versus 27 (53%) patients treated with nintedanib alone.

Diarrhea, nausea, vomiting, and abdominal pain (includes upper abdominal pain, abdominal discomfort, and abdominal pain) were the most frequent adverse events reported in 20 (38%) versus 16 (31%), in 22 (42%) versus 6 (12%), in 15 (28%) versus 6 (12%), and in 15 (28%) versus 7 (14%) patients treated with pirfenidone added to nintedanib versus nintedanib alone, respectively.

More subjects reported AST or

ALT elevations (greater than or equal to 3 times the upper limit of normal) when using pirfenidone in combination with nintedanib (n=3 (6%)) compared to nintedanib alone (n=0) .

Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib capsules were studied in a phase 3, double-blind, placebo-controlled trial (Study 5) in which 663 patients with chronic fibrosing ILDs with a progressive phenotype were randomized to receive nintedanib capsules 150 mg twice daily (n=332) or placebo (n=331) for at least 52 weeks.

At 52 weeks, the median duration of exposure was 12 months for patients in both treatment arms.

Subjects ranged in age from to 87 years (median age of 67 years).

The majority of patients were

Caucasian (74%) or Asian (25%).

Most patients were male (54%).

The most frequent serious adverse event reported in patients treated with nintedanib capsules, more than placebo, was pneumonia (4% vs. 3%).

Adverse events leading to death were reported in 3% of patients treated with nintedanib capsules and in 5% of patients treated with placebo.

No pattern was identified in the adverse events leading to death.

Adverse reactions leading to permanent dose reductions were reported in 33% of nintedanib capsules-treated patients and 4% of placebo-treated patients.

The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (16%).

Adverse reactions leading to discontinuation were reported in 20% of nintedanib capsules-treated patients and 10% of placebo-treated patients.

The most frequent adverse reaction that led to discontinuation in nintedanib capsules-treated patients was diarrhea (6%).

The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with nintedanib capsules was consistent with that observed in IPF patients.

In addition, the following adverse events were reported in nintedanib capsules more than placebo in chronic progressive fibrosing ILD: nasopharyngitis (13% vs. 12%), upper respiratory tract infection (7% vs 6%), urinary tract infection (6% vs. 4%), fatigue (10% vs. 6%), and back pain (6% vs. 5%). 1 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of nintedanib capsules.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Disorders: Drug-induced liver injury Nervous System.

Disorders: Posterior reversible encephalopathy syndrome Renal and Urinary.

Disorders: Proteinuria Skin and Subcutaneous Tissue.

Disorders: Pruritus, rash Vascular.

Disorders: Non-serious and serious bleeding events, some of which were fatal.

In IPF trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days.

A non.

• serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events.

Overdosage was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days.

Adverse events reported were consistent with the existing safety profile of nintedanib capsules.

Both patients recovered.

In case of overdosage, interrupt treatment and initiate general supportive measures as appropriate.

Recommended dosage: 150 mg taken orally twice daily approximately 12 hours apart taken with food.

Recommended dosage in patients with mild hepatic impairment (Child Pugh A): 100 mg taken orally twice daily approximately 12 hours apart taken with food.

Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions.

Prior to treatment initiation, conduct liver function tests in all patients and a pregnancy test in females of reproductive potential. 2.1 Testing Prior to Nintedanib Capsules Administration Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with Nintedanib Capsules. 2.2 Recommended Dosage The recommended dosage of Nintedanib Capsules is 150 mg taken orally twice daily administered approximately 12 hours apart.

Capsules should be taken with food and swallowed whole with liquid.

Capsules should not be chewed because of a bitter taste.

Capsules should not be opened or crushed.

If contact with the content of the capsule occurs, wash hands immediately and thoroughly.

The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.

Information for Missed Dose If a dose of Nintedanib Capsules is missed, the next dose should be taken at the next scheduled time.

Advise the patient to not make up for a missed dose.

Do not exceed the recommended maximum daily dosage of 300 mg. 2.3 Recommended Dosage for Patients with Hepatic Impairment Mild Hepatic Impairment In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of Nintedanib Capsules is 100 mg orally twice daily approximately 12 hours apart taken with food.

Moderate or Severe Hepatic Impairment Treatment with Nintedanib Capsules is not recommended. 2.4 Dosage Modification due to Adverse Reactions In addition to symptomatic treatment, if applicable, the management of adverse reactions of Nintedanib Capsules may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy.

Capsules treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage.

If a patient does not tolerate 100 mg twice daily, discontinue treatment with Nintedanib Capsules.

Dose modifications or interruptions may be necessary for liver enzyme elevations.

Conduct liver function tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin) prior to initiation of treatment with Nintedanib Capsules, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Discontinue Nintedanib Capsules in patients with AST or ALT greater than 3 times the upper limit of normal (ULN) with signs or symptoms of liver injury and for AST or ALT elevations greater than 5 times the upper limit of normal.

For AST or

ALT greater than 3 times to less than 5 times the ULN without signs of liver damage, interrupt treatment or reduce Nintedanib Capsules to 100 mg twice daily.

Once liver enzymes have returned to baseline values, treatment with Nintedanib Capsules may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily) .

In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.

mg: red-brown, opaque, oblong, soft capsules imprinted in black with "150".

They are packaged in

HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 42799-973-01 100 mg: yellow to peach, opaque, oblong, soft capsules imprinted in black with "100".

HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 42799-972-01 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Protect from exposure to high humidity and avoid excessive heat.

If repackaged, use USP tight container.

Based on findings from animal studies and its mechanism of action, nintedanib capsules can cause fetal harm when administered to a pregnant woman.

There are no data on the use of nintedanib capsules during pregnancy.

In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.

In animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively).

Malformations included abnormalities in the vasculature, urogenital, and skeletal systems.

Vasculature anomalies included missing or additional major blood vessels.

Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified).

In some fetuses, organs in the urogenital system were missing.

In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day).

Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

Based on findings from animal studies and its mechanism of action, nintedanib capsules can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential.

Counsel patients on pregnancy prevention and planning.

Verify the pregnancy status of females of reproductive potential prior to treatment with Nintedanib Capsules and during treatment as appropriate.

Nintedanib capsules can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with Nintedanib Capsules.

Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of Nintedanib Capsules.

The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.

Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.

Based on animal data, nintedanib capsules may reduce fertility in females of reproductive potential.

The safety and effectiveness of nintedanib capsules have not been established in pediatric patients for the treatment of fibrosing interstitial lung diseases.

Effectiveness was not demonstrated in a randomized, double-blind, placebo.

• controlled study conducted in 26 nintedanib capsules-treated pediatric patients aged to 17 years with fibrosing interstitial lung diseases, who were treated with nintedanib capsules based on weight.

In repeat-dose toxicology studies, young animals (mice, rats, and monkeys) dosed with nintedanib showed changes in the bone and fast-growing teeth.

Bone changes include thickening of the growth plate in all species.

These changes were fully or at least partially reversible in rats and monkeys; reversibility in mice has not been studied.

Tooth changes include broken incisors and discoloration in rodents.

These changes were irreversible after discontinuation of nintedanib treatment.

Of the total number of subjects in phase and 3 clinical studies of nintedanib capsules in IPF (Study 1, Study 2, and Study 3), 61% were and over, while 16% were and over.

In the chronic fibrosing

ILDs with a progressive phenotype clinical study (Study 5), 61% were and over, while 19% were and older.

In phase 3 studies, no overall differences in effectiveness were observed between subjects who were and over and younger subjects; no overall differences in safety were observed between subjects who were and over or and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.