FESOTERODINE FUMARATE

Fesoterodine fumarate extended-release tablet contains fesoterodine fumarate. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist. Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The molecular formula is C 30 H 41 NO 7 and its molecular weight is 527.66. The structural formula is: The asterisk (*) indicates the chiral carbon. Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water and methanol. Each fesoterodine fumarate extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, povidone, talc, titanium dioxide and xanthan gum. Additionally each 4 mg tablets contain iron oxide yellow. Image

Fesoterodine fumarate extended-release tablets are indicated for the treatment of: Overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. ( 1.1 ) Neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of age and older and weighing greater than 25 kg. ( 1.2 ) 1.1 Adult Overactive Bladder Fesoterodine fumarate extended-release tablets are indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. 1.2 Pediatric Neurogenic Detrusor Overactivity Fesoterodine fumarate extended-release tablets are indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of age and older with a body weight greater than 25 kg.

OAB in Adults: The recommended starting dosage is 4 mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of 8 mg once daily. ( 2.1 ) NDO in Pediatric Patients 6 Years and Older: Pediatric Patients Weighing Greater than 25 kg and up to 35 kg: The recommended dosage is 4 mg orally once daily. If needed, dosage may be increased to 8 mg orally once daily. (2.2) Pediatric Patients Weighing Greater than 35 kg: The recommended starting dosage is 4 mg orally once daily. After one week, increase to 8 mg orally once daily. (2.2) Adult or Pediatric Patients with Renal Impairment: Refer to the full prescribing information for recommended dosage. (2.3, 2.4) Dosage Modifications Due to Strong CYP3A4 Inhibitors: Refer to the full prescribing information for recommended dosage. ( 2.5 ) Administration: Swallow whole with liquid. Do not chew, divide, or crush. Take with or without food. ( 2.6 ) 2.1 Recommended Dosage for Adult Patients with OAB The recommended starting dosage of fesoterodine fumarate extended-release tablets in adults is 4 mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of fesoterodine fumarate extended-release tablets 8 mg once daily. For administration instructions, see Dosage and Administration ( 2.6 ). 2.2 Recommended Dosage for Pediatric Patients Aged 6 Years and Older with NDO Pediatric Patients Weighing Greater than 25 kg and up to 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets are 4 mg orally once daily. If needed, dosage may be increased to fesoterodine fumarate extended-release tablets 8 mg orally once daily. For administration instructions, s ee Dosage and Administration ( 2.6 ). Pediatric Patients Weighing Greater than 35 kg The recommended starting dosage of fesoterodine fumarate extended-release tablets are 4 mg orally once daily. After one week, increase to fesoterodine fumarate extended-release tablets 8 mg orally once daily. For administration instructions, see Dosage and Administration ( 2.6) . 2.3 Recommended Dosage in Adult Patients with Renal Impairment The recommended dosage of fesoterodine fumarate extended-release tablets in adult patients with renal impairment is described in Table 1 [see Use in Specific Populations ( 8.6 )]. For administration instructions, see Dosage and Administration ( 2.6 ). Table 1 Fesoterodine Fumarate Extended-Release Tablets Recommended Dose in Adult Patients with Renal Impairment (Administered Orally Once Daily) Estimated Creatinine Clearance 1 Recommended Dose CLcr 30 to 89 mL/min 8 mg CLcr 15 to 29 mL/min 4 mg CLcr <15 mL/min 4 mg 1 Calculate CLcr using the Cockcroft-Gault formula 2.4 Recommended Dosage in Pediatric Patients with Renal Impairment Pediatric Patients Weighing Greater than 25 kg and up to 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets in pediatric patients with renal impairment weighing greater than 25 kg and up to 35 kg is described in Table 2 [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and Administration ( 2.6 ) . Table 2 Fesoterodine Fumarate Extended-Release Tablets Recommended Dose in Pediatric Patients Aged 6 Years and Older Weighing Greater Than 25 kg and up to 35 kg With Renal Impairment (Administered Orally Once Daily) 1 Estimate GFR using a validated GFR estimating equation for the pediatric age range of the approved indication. 2 Dosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients 6 years and older. Estimated Glomerular Filtration Rate (GFR) 1 Recommended Dose 2 eGFR 30 to 89 mL/min/1.73m 2 4 mg eGFR 15 to 29 mL/min/1.73m 2 Use is Not Recommended eGFR <15 mL/min/1.73m 2 or requiring dialysis Use is Not Recommended Pediatric Patients weighing greater than 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets in pediatric patients with renal impairment weighing greater than 35 kg is described in Table 3 [see Use in Specific Populations ( 8.6 )]. For administration instructions, see Dosage and Administration ( 2.6 ) . Table 3 Fesoterodine Fumarate Extended-Release Tablets Recommended Dose in Pediatric Patients Aged 6 Years and Older Weighing Greater Than 35 kg With Renal Impairment (Administered Orally Once Daily) 1 Estimate GFR using a validated GFR estimating equation for the pediatric age range of the approved indication. 2 The recommended starting dosage of fesoterodine fumarate extended-release tablets are 4 mg orally once daily. After one week, increase to the recommended dosage of fesoterodine fumarate extended-release tablets 8 mg orally once daily. 3 Dosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients 6 years and older. Estimated GFR 1 Recommended Dose 3 eGFR 30 to 89 mL/min/1.73m 2 8 mg 2 eGFR15 to 29 mL/min/1.73m 2 4 mg eGFR <15 mL/min/1.73m 2 or requiring dialysis Use is Not Recommended 2.5 Fesoterodine Fumarate Extended-Release Tablets Dosage Modifications Due to Strong CYP3A4 Inhibitors Adult Patients with OAB The maximum recommended dosage is fesoterodine fumarate extended-release tablets 4 mg orally once daily in adult patients taking strong CYP3A4 inhibitors [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. For administration instructions, see Dosage and Administration ( 2.6 ). Pediatric Patients with NDO Pediatric Patients Weighing Greater than 25 kg and up to 35 kg The use of fesoterodine fumarate extended-release tablets in pediatric patients weighing greater than 25 kg and up to 35 kg and taking strong CYP3A4 inhibitors is not recommended [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . For administration instructions, see Dosage and Administration ( 2.6 ) . Pediatric Patients Weighing Greater than 35 kg The maximum recommended dosage is fesoterodine fumarate extended-release tablets 4 mg orally once daily in pediatric patients weighing greater than 35 kg and taking strong CYP3A4 inhibitors [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . For administration instructions, see Dosage and Administration ( 2.6 ) . 2.6 Administration Instructions Swallow fesoterodine fumarate extended-release tablets whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology ( 12.3 )].

Fesoterodine fumarate extended-release tablets are contraindicated in patients with any of the following: known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [see Clinical Pharmacology ( 12.1 )]. Reactions have included angioedema [see Warnings and Precautions ( 5.1 )]. urinary retention [see Warnings and Precautions ( 5.2 )] gastric retention [see Warnings and Precautions ( 5.3 )] uncontrolled narrow-angle glaucoma [see Warnings and Precautions ( 5.4 )] Known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules. ( 4 ) Urinary retention ( 4 ) Gastric retention ( 4 ) Uncontrolled narrow-angle glaucoma. ( 4 )

The following clinically significant adverse reactions are described elsewhere in labeling: Angioedema [see Warnings and Precautions ( 5.1 )] Urinary Retention [see Warnings and Precautions ( 5.2 )] Decreased Gastrointestinal Motility [see Warnings and Precautions ( 5.3 )] Most frequently reported adverse events with fesoterodine fumarate extended-release tablets in adult patients with OAB (≥4%) were: dry mouth (placebo, 7%; fesoterodine fumarate extended-release tablets, 4 mg, 19%; fesoterodine fumarate extended-release tablets, 8 mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate extended-release tablets, 4 mg, 4%; fesoterodine fumarate extended-release tablets, 8 mg, 6%). ( 6.1 ) Most frequently reported adverse reactions with fesoterodine fumarate extended-release tablets in pediatric patients (≥2%) with NDO were: diarrhea, urinary tract infection (UTI), dry mouth, constipation, abdominal pain, nausea, weight increased, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1- 877-993-8779 or FDA at 1-800-FDA-1088 or www.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. Adult Overactive Bladder (OAB) The safety of fesoterodine fumarate extended-release tablets was evaluated in Phase 2 and 3 controlled trials in a total of 2,859 patients with overactive bladder, of which 2,288 were treated with fesoterodine fumarate extended-release tablets. Of this total, 782 received fesoterodine fumarate extended-release tablets 4 mg/day, and 785 received fesoterodine fumarate extended-release tablets 8 mg/day with treatment periods of 8 weeks or 12 weeks. Approximately 80% of these patients had greater than 10 weeks of exposure to fesoterodine fumarate extended-release tablets in these trials. A total of 1,964 patients participated in two 12 week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received fesoterodine fumarate extended-release tablets 4 mg/day and 566 patients received fesoterodine fumarate extended-release tablets 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, fesoterodine fumarate 4 mg, and fesoterodine fumarate 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving fesoterodine fumarate who reported one serious adverse reaction each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with fesoterodine fumarate was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, fesoterodine fumarate 4 mg, and fesoterodine fumarate 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment. The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day. Table 4 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with fesoterodine fumarate 4 mg or 8 mg once daily for up to 12 weeks. Table 4 Adverse Events with an Incidence Exceeding the Placebo Rate and Reported by ≥1% of Patients From Double-Blind, Placebo-Controlled Phase 3 Trials of 12 Weeks Treatment Duration System organ class/Preferred term Placebo N=554 % Fesoterodine Fumarate Extended-Release Tablets 4 mg/day N=554 % Fesoterodine Fumarate Extended-Release Tablets 8 mg/day N=566 % Gastrointestinal disorders Dry mouth Constipation Dyspepsia Nausea 7 2 0.5 1.3 18.8 4.2 1.6 0.7 34.6 6 2.3 1.9 Abdominal pain upper 0.5 1.1 0.5 Infections Urinary tract infection 3.1 3.2 4.2 Upper respiratory tract infection 2.2 2.5 1.8 Eye disorders Dry eyes 0 1.4 3.7 Renal and urinary disorders Dysuria Urinary retention 0.7 0.2 1.3 1.1 1.6 1.4 Respiratory disorders Cough Dry throat 0.5 0.4 1.6 0.9 0.9 2.3 General disorders Edema peripheral 0.7 0.7 1.2 Musculoskeletal disorders Back pain 0.4 2 0.9 Psychiatric disorders Insomnia 0.5 1.3 0.4 Investigations ALT increased GGT increased 0.9 0.4 0.5 0.4 1.2 1.2 Skin disorders Rash 0.5 0.7 1.1 ALT = alanine aminotransferase; GGT = gamma glutamyltransferase Patients also received fesoterodine fumarate extended-release tablets for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received fesoterodine fumarate extended-release tablets for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12 week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases). Pediatric Neurogenic Detrusor Overactivity (NDO) The safety of fesoterodine fumarate extended-release tablets was evaluated in a total of 131 pediatric patients with NDO. Patients received fesoterodine fumarate extended-release tablets 4 mg or fesoterodine fumarate extended-release tablets 8 mg orally once daily in two clinical trials (Studies 3 and 4). Study 3 was a Phase 3 study in pediatric patients with NDO from 6 years to 17 years of age and weighing greater than 25 kg. This study consisted of a 12 week efficacy phase, in which 84 patients received fesoterodine fumarate extended-release tablets, followed by a 12 week safety extension phase, in which 103 patients received fesoterodine fumarate extended-release tablets. Of the 103 patients who received fesoterodine fumarate extended-release tablets in the safety extension phase, 67 continued fesoterodine fumarate extended-release tablets from the efficacy phase and 36 switched from an active comparator in the efficacy phase to fesoterodine fumarate extended-release tablets in the safety extension phase. Study 4 (N=11) was an 8 week, Phase 2 pharmacokinetic (PK) and safety study in pediatric patients with NDO from 8 years to 17 years of age. The most commonly reported adverse reactions in pediatric patients with NDO who received fesoterodine fumarate extended-release tablets 4 mg or 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased and headache. Table 5 lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group in the Study 3 efficacy phase. Table 5 Adverse Reactions Reported in ≥2% of Patients with NDO Aged 6 Years to 17 Years in the 12 Week Efficacy Phase of Study 3 † Includes abdominal pain and abdominal pain upper Preferred term Fesoterodine Fumarate Extended-Release Tablets 4 mg (N=42) % Fesoterodine Fumarate Extended-Release Tablets 8 mg (N=42) % Diarrhea 11.9 7.1 Urinary tract infection 9.5 2.4 Dry mouth 7.1 9.5 Constipation 7.1 7.1 Abdominal pain † 7.1 4.8 Nausea 4.8 2.4 Weight increased 4.8 0 Headache 4.8 7.1 Ophthalmological Adverse Reactions Ophthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were reported in 8 of 131 (6.1%) pediatric patients with NDO who received fesoterodine fumarate extended-release tablets 4 mg or fesoterodine fumarate extended-release tablets 8 mg in Study 3 (both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result in discontinuation of fesoterodine fumarate extended-release tablets in any patient. Increases in Heart Rate Increases in heart rate were reported in pediatric patients with NDO who received fesoterodine fumarate extended-release tablets 4 mg and fesoterodine fumarate extended-release tablets 8 mg in Study 3. The mean heart data are described in Table 6. Table 6 Mean Baseline and Mean Changes From Baseline in Heart Rate in Pediatric Patients Weighing Greater Than 25 kg in Study 3 1 Heart rate expressed as the mean of the baseline measurement and the mean at each study visit and mean changes from baseline at each study visit by original treatment group in patients with complete follow-up at all study visits. Study visit Mean heart rate in beats per minute 1 (mean change from baseline) Fesoterodine Fumarate Extended-Release Tablets 4 mg Fesoterodine Fumarate Extended-Release Tablets 8 mg Baseline 88.6 84.2 Week 4 93.8 (+5.2) 94.0 (+9.8) Week 12 94.8 (+6.2) 94.0 (+9.8) Week 24 90.4 (+1.8) 90.8 (+6.5) The proportion of patients with heart rates greater than the 99 th percentile for age also increased from baseline in patients who received fesoterodine fumarate extended-release tablets 4 mg and fesoterodine fumarate extended-release tablets 8 mg in Study 3. These data are described in Table 7. Table 7 Proportion of Pediatric Patients With Heart Rate Greater Than the 99 th Percentile for Age and Weighing Greater Than 25 kg in Study 3 * Week 12 comprises patients who received fesoterodine fumarate extended-release tablets for 12 weeks after being originally randomized to fesoterodine fumarate extended-release tablets 4 mg and 8 mg and patients originally randomized to active comparator and subsequently transitioned to fesoterodine fumarate extended-release tablets 4 mg and 8 mg for 12 weeks. Study visit Proportion of patients with heart rate >99th percentile for age Fesoterodine Fumarate Extended-Release Tablets 4 mg Fesoterodine Fumarate Extended-Release Tablets 8 mg Baseline 2.4% 2.4% Week 4 8.1% 12.2% Week 12* 7.5% 11.5% Week 24 3.3% 2.7% Increases from baseline in the proportion of patients with a heart rate greater than the 99 th percentile for age were most pronounced in patients less than 12 years of age who received fesoterodine fumarate extended-release tablets 8 mg. Increases in heart rate in patients who received fesoterodine fumarate extended-release tablets 4 mg and fesoterodine fumarate extended-release tablets 8 mg in Study 3 were not associated with clinical symptoms and did not result in discontinuation of therapy with fesoterodine fumarate extended-release tablets. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fesoterodine fumarate extended-release tablets. 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. Cardiac disorders: Palpitations Central nervous system disorders: Dizziness, headache, somnolence Eye disorders: Blurred vision Gastrointestinal disorders: Hypoaesthesia oral General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema Psychiatric disorders: Confusional state Skin and subcutaneous tissue disorders: Urticaria, pruritus

7.1 Antimuscarinic Drugs Coadministration of fesoterodine fumarate with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. 7.2 CYP3A4 Inhibitors Doses of fesoterodine fumarate extended-release tablets greater than 4 mg are not recommended in adult patients taking strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin [see Dosage and Administration ( 2.5 )]. The fesoterodine fumarate extended-release tablets dose in pediatric patients taking strong CYP3A4 inhibitors is recommended to be reduced to 4 mg once daily in patients >35 kg and is not recommended in patients weighing greater than 25 kg and up to 35 kg [see Dosage and Administration ( 2.5 )]. In a study in adults, coadministration of the strong CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (C max ) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole [see Clinical Pharmacology ( 12.3 )]. There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in C max and AUC of the active metabolite of fesoterodine was approximately 19% (11% to 28%) and 27% (18% to 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). The effect of weak CYP3A4 inhibitors (e.g., cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors [see Clinical Pharmacology ( 12.3 )] . 7.3 CYP3A4 Inducers No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once a day, C max and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate 8 mg. The terminal half-life of the active metabolite was not changed. 7.4 CYP2D6 Inhibitors The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C max and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors. 7.5 Drugs Metabolized by Cytochrome P450 In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems [see Clinical Pharmacology ( 12.3 )] . 7.6 Oral Contraceptives In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel [see Clinical Pharmacology ( 12.3 )] . 7.7 Warfarin A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued [see Clinical Pharmacology ( 12.3 )] . 7.8 Drug-Laboratory Test Interactions Interactions between fesoterodine fumarate and laboratory tests have not been studied.