Flomax for kidney stone

Study of FLOMAX® Versus Placebo in Female Patients With Lower Urinary Tract Symptoms (LUTS) With a Significant Component of Voiding Symptoms

Inclusion Criteria:

  • Adult women, 18 years of age or older, currently diagnosed with LUTS with a significant component of voiding symptoms
  • The Patient must be diagnosed with one of the following: hesitancy, intermittency, difficulty in bladder emptying, or straining to void
  • Patients must have had an AUA Symptom Score of 13 or higher
  • Obstruction component of AUA Symptom Score (Items 1, 3, 5, and 6) had to be 5 points or higher
  • Patients that are currently taking alpha-blockers or anticholinergics must discontinue the drugs at least 2 weeks prior to Visit 1
  • Patients should show compliance of greater than or equal to 80% with placebo usage
  • Patients should be surgically sterile, or 2 years postmenopausal, or practicing a medically acceptable method of birth control
  • Patients must have a negative urine Beta Human Chorionic Gonadotropin (beta-HCG)
  • Patients must be able to provide written informed consent prior to participation in the study in accordance with regulatory requirements
  • Patients must be judged by the investigator to be reliable and should comply with all tests and examinations stipulated in the protocol
  • All patients should be able to understand and read English

Exclusion Criteria:

  • Patients who presented with an active urinary tract infection or who had presented with two or more culture positive urinary tract infections within 6 months of the study
  • Patients with significant prolapse beyond the hymenal ring, per the investigator’s judgment
  • Patients who had taken anticholinergic medications for the treatment of other urologic conditions and had not discontinued their use 2 weeks prior to study entry
  • Patients who had a history or active condition of renal or urethral calculi, urethral colic, mechanical outlet obstruction (i.e., bladder neck contracture or stricture, bladder tumor, or bladder calculi) 3 months prior to study entry
  • Patients with a history of bladder, vaginal or urethral surgery in the last 6 months
  • Patients who have a history of microscopic hematuria and not had a recent work-up including cystoscopy and upper urinary tract study (within 6 months of screening) or a diagnosis of a condition that may exclude the patient in the opinion of the investigator
  • Abnormal urinalysis as defined by the following mid-stream, clean-catch specimen results:

    • A bacterial colony count of greater than 100,000/ml.
    • More than 10 leukocytes per high power field with more than two granular casts per high power field.
    • More than 10 red blood cells (non-menstrual tainted urine sample) per high power field.
    • Proteinuria >+1 (equivalent to >30 mg/dL)
  • Patients presenting with any of the following: history of a neurogenic bladder due to any neurologic condition that might involve the lower urinary tract, active urinary stone disease, previous pelvic radiotherapy, perirectal inflammatory disorder or inflammatory bowel disease
  • Patients that had a history of sexually transmitted diseases of the genitourinary system such as syphilis, herpes, gonorrhea, chlamydia, mycoplasma, trichomonas (within 3 months of the study) or any other diagnosis that in the opinion of the investigator may have excluded the patient
  • Patients that are pregnant or breast-feeding
  • The Patient has significant pelvic pain that demands treatment with narcotics
  • Large fluctuations in LUTS symptoms over the last 6 months (i.e., symptoms appearing and disappearing with unusual rapidity)
  • Any baseline (Visit 1) laboratory serum test with the following values: Hemoglobin: <11.0 g/dL, Leukocytes: <3,000 per mm3, Liver enzymes : more than two times the upper limit of normal at baseline (Visit 1). Serum creatinine more than two times the upper limit of normal at baseline (Visit 1)
  • Patients with a diagnosis of cancer, except basal cell carcinoma, within the past 5 years. (Note: Contact the Trial Clinical Monitor with any specific or special circumstances regarding the entry of a cancer patient.)
  • Participation in another drug study within 4 weeks of baseline (Visit 1)
  • Clinically relevant conditions which may interfere with the patient’s ability to participate in the study including, but not limited to, the following: neurologic, gastrointestinal, cardiovascular, hepatic, renal, psychiatric, hematologic or respiratory disease and clinically relevant laboratory abnormalities not mentioned above (e.g., hematuria) based upon the clinical judgment of the investigator
  • Patients who have been receiving cimetidine, ranitidine and warfarin medications within 2 weeks of screening and who would potentially use such medication during the course of the trial
  • Patients with known hypersensitivity to FLOMAX® (tamsulosin hydrochloride) or other alpha-blockers
  • Patients with a history of myocardial infarction within 6 months of baseline (Visit 1)
  • Patients with uncontrolled hypertension (systolic >160 mmHg, diastolic >100 mmHg) and patients with severe hypotension (systolic <90 mmHg) after 5 minutes of sitting
  • Patients who have been using the following drugs, within 2 weeks prior to screening (Visit 1), and who are unable to discontinue these drugs over the course of the study

    1. Alpha-adrenergic blocking agents
    2. Alpha-adrenergic medication
    3. Drugs with systemic anticholinergic activity including antihistamines. Antihistamines allowed are Allegra®, Claritin® and Zyrtec®
    4. Antispasmodics or muscle relaxants
    5. Parasympathomimetics, cholinomimetics, and/or similar drugs
  • Patients with poorly controlled diabetes mellitus based upon urine with 2+ (or greater) glucose on urinalysis, performed at screening (Visit 1).
  • Patients who suffer from neurological diseases affecting the bladder (i.e., multiple sclerosis, Parkinson’s disease, stroke, and any bladder trauma that may have been an exclusion criterion in the opinion of the investigator)
  • Patients that have a neurological impairment or psychiatric disorder that prevents their comprehension of consent and their ability to comply with the protocol
  • Patients who had been diagnosed with interstitial cystitis according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria
  • Patients that had a history of urethral syndrome whose treatment was other than dilation. Patients treated by dilation 3 months prior to study entry were allowed to participate in the study

Flomax

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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 incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg FLOMAX capsules were used. These studies evaluated safety in 1783 patients treated with FLOMAX capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either FLOMAX capsules 0.4 mg or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men.

Table 1: Treatment-Emergent* Adverse Events Occurring in ≥2% of FLOMAX Capsules or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies

Signs And Symptoms Of Orthostasis

Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test.

Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received FLOMAX capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received FLOMAX capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1).

In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the FLOMAX capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the FLOMAX capsules 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group.

Because orthostasis was detected more frequently in FLOMAX capsule-treated patients than in placebo recipients, there is a potential risk of syncope .

Abnormal Ejaculation

Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with FLOMAX capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of FLOMAX capsules because of abnormal ejaculation was also dose-dependent, with 8 of 492 patients (1.6%) in the 0.8 mg group and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation.

Laboratory Tests

No laboratory test interactions with FLOMAX capsules are known. Treatment with FLOMAX capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FLOMAX 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to FLOMAX capsules. Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period. During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 blocker therapy .

Read the entire FDA prescribing information for Flomax (Tamsulosin Hydrochloride)

The Effect of Tamsulosin on the Resting Tone and the Contractile Behaviour of the Female Urethra: A Functional Urodynamic Study in Healthy Women

Aims: The aim of this functional urodynamic experiment was to study the effect of the selective α1A-blocker tamsulosin on the urethral pressure in healthy human females and assessed first the resting urethral pressure and second the urethral contractility in response to magnetic stimulation of the sacral roots.

Methods: 11 healthy female subjects gave their written informed consent and were included. A microtip pressure transducer catheter was inserted into the bladder and three baseline urethral pressure profiles were obtained. Another three urethral pressure profiles were recorded while magnetic single pulse stimulation of the sacral roots was performed above the motor threshold of the pelvic floor to evoke reproducible urethral contractions. Then the subjects received 0.4 mg of tamsulosin and the entire protocol was repeated 6 hours after drug administration. Cardiovascular monitoring was obtained during the baseline and follow-up measurements. Mean and maximal urethral pressure values calculated over the entire urethra, mean pressure values calculated over the proximal, middle and distal third of the urethra and the pressure amplitudes to magnetic stimulation at baseline were statistically compared to the follow-up measurements with tamsulosin.

Results: The oral administration of tamsulosin did not change the systemic blood pressure, but did significantly reduce the mean and maximal urethral pressure acquired over the entire urethra. When the proximal, middle and distal third of the urethra were analysed separately, there was a significant pressure reduction in all three segments. Amplitudes of the urethral contractions evoked by sacral magnetic stimulation remained unchanged after tamsulosin.

Conclusions: These data show a significant relaxing effect of tamsulosin on the resting urethral tone in healthy females in vivo. These results may suggest tamsulosin as a new pharmacological approach to treat urinary retention due to overactive or non-relaxing urethra in women.

CLINICAL PHARMACOLOGY

Mechanism Of Action

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype.

FLOMAX capsules are not intended for use as an antihypertensive drug.

Pharmacodynamics

Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH .

Pharmacokinetics

The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg.

Absorption

Absorption of tamsulosin hydrochloride from FLOMAX capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing.

Effect Of Food

The time to maximum concentration (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when FLOMAX capsules are administered with food. Taking FLOMAX capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions (Figure 1).

Figure 1: Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single- Dose Administration of FLOMAX Capsules 0.4 mg Under Fasted and Fed Conditions (n=8)

The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a FLOMAX capsule is taken with a light breakfast or a high-fat breakfast (Table 2).

Table 2: Mean (± S.D.) Pharmacokinetic Parameters Following FLOMAX Capsules 0.4 mg Once Daily or 0.8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted

Distribution

The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.

Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs.

Metabolism

There is no enantiomeric bioconversion from tamsulosin hydrochloride to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin . The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5-alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal.

Excretion

On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with FLOMAX capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h).

Specific Populations

Pediatric use

FLOMAX capsules are not indicated for use in pediatric populations .

Geriatric (Age) Use

Cross-study comparison of FLOMAX capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years .

Renal impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30≤ CLcr <70 mL/min/1.73 m²) or moderate-severe (10≤ CLcr

<30 mL/min/1.73 m²) renal impairment and 6 normal subjects (CLcr >90 mL/min/1.73 m²). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m²) have not been studied .

Hepatic impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic impairment .

Drug Interactions

Cytochrome P450 inhibition

Strong And Moderate Inhibitors Of CYP3A4 Or CYP2D6

The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for 5 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively . The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated .

The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively . A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) .

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated .

The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors .

Cimetidine

The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 10 healthy volunteers (age range 21 to 38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) .

Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected .

PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents, including FLOMAX, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension .

Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules .

Nifedipine, Atenolol, Enalapril

In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, atenolol, or enalapril for at least 3 months, FLOMAX capsules 0.4 mg for 7 days followed by FLOMAX capsules 0.8 mg for another 7 days (n=8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril .

Digoxin And Theophylline

In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving FLOMAX capsules 0.4 mg/day for 2 days, followed by FLOMAX capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline .

Furosemide

The pharmacokinetic and pharmacodynamic interaction between FLOMAX capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range 21 to 40 years). FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage .

Clinical Studies

Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe.

In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies (Study 1 and Study 2 ), 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction.

Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose.

Table 3: Mean (±S.D.) Changes from Baseline to Week 13 in Total AUA Symptom Score* and Peak Urine Flow Rate (mL/sec)

Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B).

In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo-controlled, 40-week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg, and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg, and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year.

Figure 2A: Mean Change from Baseline in Total AUA Symptom Score (0–35) Study 1

* indicates significant difference from placebo (p-value ≤0.050).

B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0.

Subsequent values are observed cases.

LOCF = Last observation carried forward for patients not completing the 13-week study.

Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.

Note: Total AUA Symptom Scores range from 0 to 35.

Figure 2B: Mean Change from Baseline in Total AUA Symptom Score (0–35) Study 2

* indicates significant difference from placebo (p-value ≤0.050).

Baseline measurement was taken Week 0. Subsequent values are observed cases.

LOCF = Last observation carried forward for patients not completing the 13-week study.

Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.

Note: Total AUA Symptom Scores range from 0 to 35.

Figure 3A: Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1

* indicates significant difference from placebo (p-value ≤0.050).

B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0.

Subsequent values are observed cases.

LOCF = Last observation carried forward for patients not completing the 13-week study.

Note: The uroflowmetry assessments at Week 0 were recorded 4 to 8 hours after patients received the first dose of double-blind medication.

Measurements at each visit were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration).

Note: Patients in the 0.8 mg treatment groups received 0.4 mg for the first week.

Figure 3B: Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2

* indicates significant difference from placebo (p-value ≤0.050).

Baseline measurement was taken Week 0. Subsequent values are observed cases.

LOCF = Last observation carried forward for patients not completing the 13-week study.

Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week.

Note: Week 1 and Week 2 measurements were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration).

All other visits were scheduled 24 to 27 hours after dosing (approximate trough tamsulosin concentration).

June 29, 2018

Can Tamsulosin Get That STONE to Drop?

Written by Anand Swaminathan REBEL EM Medical Category: Renal and Genitourinary

Background: Ureteric (renal) colic is a common, painful condition encountered in the Emergency Department (ED). Sustained contraction of smooth muscle in the ureter as a kidney stone passes the length of the ureter leads to pain. The majority of stones will pass spontaneously (i.e. without urologic intervention). For over a decade, calcium channel blockers (i.e. nifedipine) and, more commonly, alpha adrenoreceptor antagonists (i.e. tamsulosin) have been employed in the treatment of ureteral colic for their potential ability to increase stone passage, reduce pain medication use and reduce urologic interventions. These interventions were mostly based on poor methodologic studies and meta-analyses of these flawed studies (Hollingsworth 2016)

Over the past 3-4 years, a small number of higher-quality RCTs have been published (Ferre 2009, Pickard 2015, Furyk 2016). These studies have demonstrated a lack of benefit for routine use of alpha blockers. However, secondary outcomes suggest a possible benefit in larger stones (> 6 mm). In spite of recent multiple studies, the use of alpha blockers remains an area of active debate.

Article: Meltzer, AC et al. Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial. JAMA Intern Med 2018 PMID: 29913020

Clinical Question: Is tamsulosin effective in facilitating the ureteral stone expulsion in ED patients presenting with stones < 9 mm in diameter?

Population: Adults > 18 years of age presenting to the ED with a symptomatic urinary stone determined by computed tomography (CT) to be < 9 m in diameter and located in the ureter.

Outcomes:

  • Primary: Stone passage based on visualization or capture by day 28
  • Secondary: Stone passed on follow up CT scan, Crossover to open-label tamsulosin, time to stone passage, return to work, use of analgesic medication, hospitalization, surgical intervention and repeated ED visit for urinary stones

Intervention: Tamsulosin 0.4 mg q24

Control: Matched placebo

Design: Multicenter, randomized, double-blind, placebo-controlled study

Excluded: Patients requiring/desiring immediate surgical management, UTI, Prior GU surgery, pregnant patients, breastfeeding mothers, prior tamsulosin hypersensitivity, current use of alpha-blockers or calcium channel blockers, current use of steroids, stone > 9 mm, prior treatment for current ureteral stone, use of vardenafil (contraindication to tamsulosin), known renal insufficiency, fever > 101.5, floppy iris syndrome, planned cataract surgery within 60 days, prisoners, prior enrollment in study

Primary Results

  • 512 patients randomized
    • 267 patients to tamsulosin
    • 245 patients to placebo
  • 15 patients lost to follow up
  • Stone Size
    • Mean diameter of symptomatic urinary stone was 3.8mm
    • 26% of stones > 5 mm

Critical Findings:

  • Stone passage as reported by patient (Primary Outcome)
    • Tamsulosin 49.6% vs. placebo 47.3%
    • Relative Risk: 1.05 (95% CI 0.87 – 1.27)
    • No statistically significant difference
  • There was no significant difference in any of the secondary outcomes
  • Passage based on symptomatic stone size (preplanned subgroup analysis)
    • No statistically significant difference

  • Adverse events
    • There was more dizziness amongst patients receiving tamsulosin
    • Amongst males, there was a significantly higher rate of abnormalities with ejaculation in the tamuslosin arm (18.2% vs 7.4%)

Strengths:

  • Asks a clinically important, patient centered question
  • Multicenter study
  • Largest RCT to date on this topic
  • Randomization and blinding appropriately performed
  • Study was well protected against the risk of bias (i.e. concealed allocation, masking of patients, study personnel, and outcome assessors, intention-to-treat analysis, and near complete follow-up)
  • A pre-planned exploratory analysis of subgroups was also performed including size of stone and location of stone in the ureter
  • Baseline characteristics were similar between groups including stone size
  • Enrolled participants with stones in any part of the ureter to increase generalizability of study
  • Study in 2 phases. Phase 1 (single-center) was used to determine passage rate at 28 days in placebo arm in order to establish a target sample size to find a 15% absolute increase in primary outcome in the tamsulosin arm
  • Follow up to stone passage at 28 days (primary outcome) was excellent. Less than 3% of patients were lost
  • Almost 50% of patients (238/512) underwent repeat CT scanning at 28 days to assess for stone passage

Limitations:

  • The study only included patients with CT confirmed ureteral stones. This may exclude a large group of patients in whom ureteral colic was clinically suspected and the provider did not deem a CT was necessary
  • Study enrollment only available certain hours of the day (ranged from 60-116 hours of availability/week depending on site)
  • While most baseline characteristics were similar, some were not. More patients in the placebo arm had multiple stones, more patients in the tamsulosin arm had distal ureteral stones
  • Patients lost to follow up were excluded from the analysis. Instead, investigators could have included them with outcomes matching the null-hypothesis
  • Target absolute difference may have been set too high. A smaller but still clinically important difference may still be possible
  • Self-reported adherence to study medication was 82.9% by day 15 and 72.9% by day 28. ≈20% of study population was not using medication at 2 weeks
  • In cases in which there is more than one stone noted on the CT scan, the physician treating the patient will determine the likely location and dimensions of the stone causing symptoms by reviewing the patient’s ED record.
  • Most stones were small (75% < 5 mm)

Discussion:

  • The majority of patients (≈75%) in this study had stones < 5 mm. A recent RDCT of ≈ 3300 patients with distal ureteral stones randomized to tamsulosin vs placebo for 4 weeks. 2/3rds of the enrolled patients had stones > 5mm in size. A higher rate of stone passage was seen with tamsulosin (86% vs 79%) for distal ureteral stones. In a subgroup analysis stones >5mm also showed statistically significant benefit with tamsulosin (85.6% vs 74.5%; OR 2.05; 95% CI 1.65 – 2.54). (Ye 2017)
  • It is important to note that the idea that larger stones will benefit is based on secondary and exploratory analyses only. Additionally, the Ye article is limited as only distal ureteral stones were included. A RDCT primarily examining larger stones is needed.
  • Even if larger stones will benefit from tamsulosin, the application of this information is limited as it would require us to return to a “CT all ureteral colic patients” approach to management. This would increase radiation exposure and resource utilization with only a small portion of patients benefiting.

Authors Conclusions:

“Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised.”

Our Conclusions: We agree with the authors conclusions. This well-done, RDCT did not demonstrate an advantage to medical expulsion therapy with tamsulosin in comparison to placebo at 28 days.

Potential to Impact Current Practice: Current urology guidelines recommend the addition of tamuslosin in the treatment of ureteral colic mainly based on poor quality studies and systematic reviews and meta-analyses including these poorly done studies. This study adds to the growing, high-quality evidence that tamsulosin offers no significant benefit and further challenges current practices.

Bottom Line: Tamsulosin should not routinely be prescribed to patients with ureteral colic and, at this point, it is unclear if there is any subgroup that may benefit. There will be continued conjecture that larger stones may benefit due to inconsistency in the literature and the absence of a RDCT primarily looking at passage of larger stones.

  • EM Lit of Note: Another Failure for Tamsulosin
  • EM Lit of Note: Finally, an End to Tamsulosin for Renal Colic?
  • REBEL EM: Does Use of Tamsulosin in Renal Colic Facilitate Stone Passage?
  • Core EM: Medical Expulsive Therapy (MET) in Renal Colic
  • Core EM: Use of Alpha Blockers in Ureteric Colic – Systematic Review + Meta-Analysis
  • Justin Morgenstern at First10EM: Tamsulosin for Kidney Stones – The STONE Trial
  • Simon Carley at St. Emlyn’s: JC – Tamsulosin and Renal Colic
  • Ken Milne at The SGEM: SGEM #230 – Tamsulosin – You’ve Lost that Loving Feeling – For Renal Colic
  1. Hollingsworth JM et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ 2016. PMID: 27908918
  2. Al-Ansari et al. Efficacy of Tamsulosin in the Management of Lower Ureteral Stones: A Randomized Double-blind Placebo-controlled Study of 100 Patients. Urology 2010; 75: 4-8. PMID: 20109697
  3. Ferre RM et al. Tamsulosin for Ureteral Stones in the ED: a Randomized, Controlled Trial. Ann of EM 2009; 54: 432-9. PMID: 19200622
  4. Furyk JS et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016; 67(1): 86-95. PMID: 26194935
  5. Hermanns T et al. Is There a Role for Tamsulosin in the Treatment of Distal Ureteral Stones of 7 mm or less? Results of Randomised, Double-Blind, Placebo-Controlled Trial. European Urology 2009; 56(3): 407-12. PMID: 19375849
  6. Picard R et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015; 386(9991): 341-9. PMID: 25998582
  7. Segura JW et al. The American Urological Association. Ureteral Stones Clinical Guidelines Panel summary report on the management of ureteral calculi. J Urol. 1997;158(5):1915-1921. PMID: 9334635
  8. Singh A et al. A Systemic Review of Medical Therapy to Facilitate Passage of Ureteral Calculi. Ann of EM 2007; 50: 552-63. PMID: 17681643
  9. Vincendeau S et al. Tamsulosin hydrochloride vs Placebo for Management of Distal Ureteral Stones. Arch Intern Med 2010; 170(22): 2021-7. PMID: 21149761
  10. Ye Z et al. Efficacy and safety of tamsulosin in medical expulsion therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2017. PMID: 29137830

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

Cite this article as: Anand Swaminathan, “Can Tamsulosin Get That STONE to Drop?”, REBEL EM blog, June 29, 2018. Available at: https://rebelem.com/can-tamsulosin-get-that-stone-to-drop/. The following two tabs change content below.

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Anand Swaminathan

Clinical Assistant Professor of Emergency Medicine at St. Joe’s Regional Medical Center (Paterson, NJ) REBEL EM Associate Editor and Author

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Recent clinical trial finds tamsulosin not effective in kidney stone passage

Credit: CC0 Public Domain

The latest research into finding medications to aid the passage of ureteral or kidney stones has shown that tamsulosin is not effective for patients across the board. Previously approved to help men experiencing enlarged prostates, tamsulosin is an Alpha-1 blocker that, in small studies, had been found to be a promising aid to passing kidney stones.

A recent multi-center clinical trial funded by the National Institute for Diabetes and Digestive and Kidney Diseases, revealed no significant support for the use of tamsulosin for kidney stones. The results, published in JAMA Internal Medicine, found no significant effect of patient-reported passage or capture of the stone.

“There is no known medication for helping patients pass kidney stones,” explained Andrew Meltzer, MD, associate professor of emergency medicine at the George Washington University (GW) School of Medicine and Health Sciences. Current guidelines by the American Urological Society call for all patients with stones to receive tamsulosin to help facilitate passage. “We will likely have to change the guidelines regarding which groups of patients should receive the medication,” he said.

During the six-year trial, patients presented to the emergency department describing pain associated with stones. One tablet of tamsulosin was administered per day for 28 days with few patients reporting stone passage.

According to Meltzer, the medication isn’t completely out of question. Various subgroup analyses suggest that tamsulosin may work in certain subgroups of patients—those with larger stones or with distal stones.

About 10 percent of people suffer from kidney stones, which cause excruciating pain that many compare to child birth. It is estimated that the annual medical costs associated with stones are approximately $5 billion.

“We are still looking for noninvasive ways to manage patients who have ureteral stones in order to promote passage and decrease complications and pain,” Meltzer said.

The article, “Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial,” is published in JAMA Internal Medicine.

Explore further

Bust up big kidney stones with tamsulosin More information: Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial, JAMA Internal Medicine (2018). doi:10.1001/jamainternmed.2018.2259 , jamanetwork.com/journals/jamai … /fullarticle/2684477 Journal information: JAMA Internal Medicine Provided by George Washington University Citation: Recent clinical trial finds tamsulosin not effective in kidney stone passage (2018, June 18) retrieved 2 February 2020 from https://medicalxpress.com/news/2018-06-clinical-trial-tamsulosin-effective-kidney.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

This too shall pass—or will it?

Kidney stones are painful. Childbirth painful. In addition to pain meds, how can we help you pass that stone quickly? Now we may know.

Kidney stones (nephrolithiasis) occur in 5% – 12% of the population and frequently on Friday afternoons. Eighty percent of them are calcium oxalate stones and interestingly, 20% are in the ureter at the time you come to the ER for help. They all hurt.

You are often on your own at home to deal with them, as we have become more comfortable managing stones for outpatients, but you need to know what medications you need.

Stones that are less than 5 mm in size have an 85% chance of passing on their own. Those that are 5 – 10 mm have a 50% chance, and those larger than 8 mm have a 20% chance.

Generic Flomax (tamsulosin), will help you pass stones less than 10 mm in size, especially if your stone is already far down in the ureter.

But sometimes the stones are more stubborn—is there anything else we can do?

A recent study looked at adding prednisolone to tamsulosin to help you pass a stone. Here is what we learned:

Tamsulosin 0.4 mg + 5 mg of prednisolone (equivalent to 5 mg of prednisone) was compared to watchful waiting (all patients received intravenous Toradol (ketorolac) as needed for pain).

The group of folks with kidney stones who received the tamsulosin + prednisolone passed the stone on their own 70% of the time (compared to only 32% in the group who did nothing) and had less pain.

These are two cheap, safe oral medications. If you are being tortured by a stone, this is a no-brainer.

Dr O.

You can find 30 capsules of tamsulosin for under $20 at many pharmacies with a coupon or using a pharmacy membership program. Prednisolone is under $10 for 30 tablets in most cases, sometimes as low as $5. Both medications should be covered by most insurance plans under Tier 1, meaning you’ll pay only your lowest copay.

  • About tamsulosin

    Type of medicine An alpha-blocker
    Used for Enlargement of the prostate gland in men
    Also called Cositam®; Contiflo®; Diffundox®; Faramsil®; Flectone®; Flomax® Relief; Flomaxtra®; Pamsvax®; Petyme®; Pinexel®; Prosurin®; Tabphyn®; Tamfrex®; Tamurex®
    Combination brands: Combodart® (this contains tamsulosin in combination with dutasteride); Vesomni® (this contains tamsulosin in combination with solifenacin)
    Available as Prolonged-release tablets and capsules

    The prostate gland commonly becomes larger in older men. Prostate gland enlargement is also called benign prostatic hyperplasia (BPH). The prostate is situated close to the bladder, so its enlargement can cause problems with passing urine. Common symptoms that are experienced are having to wait before your urine starts to flow, taking longer at the toilet, dribbling urine, and a feeling that your bladder is not quite empty.

    Tamsulosin works by relaxing the muscles around your bladder and prostate gland so that you can pass urine more easily.

    Sometimes, more than one type of medicine is needed to control the symptoms of prostate enlargement. Tamsulosin is available in combination with other medicines for prostate enlargement. The combination brand called Combodart® contains tamsulosin with a medicine called dutasteride, and the combination brand called Vesomni® contains tamsulosin with a medicine called solifenacin. These brands may give better relief of symptoms than tamsulosin alone.

    Tamsulosin is also available from a pharmacy as a medicine called Flomax® Relief. The pharmacist will need to ask a number of questions about your medical history to make sure that tamsulosin is suitable for you. You will also need to be diagnosed by your doctor as having an enlarged prostate gland.

    Before taking tamsulosin

    Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking tamsulosin it is important that your doctor or pharmacist knows:

    • If you ever feel dizzy or faint when you stand up, or if you have ever fainted after passing urine.
    • If you need to have cataract eye surgery.
    • If you have any problems with the way your liver works, or any problems with the way your kidneys work.
    • If you have ever had an allergic reaction to a medicine.
    • If you are taking or using any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines.

    How to take tamsulosin

    • Before you start the treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about tamsulosin and will provide you with a full list of the side-effects which you may experience from taking it.
    • Take tamsulosin exactly as your doctor or pharmacist tells you to. Swallow each dose with a drink of water – do not crush, break, or chew the tablets/capsules.
    • Your first dose of tamsulosin may make you feel dizzy or faint, so it is important that you take it just before you go to bed. If you feel dizzy or weary, or if you start sweating, remain lying down until these symptoms have completely gone.
    • Take one tablet/capsule every day. After the first dose, you can take your dose at a time of day that best suits you. Although you can take tamsulosin either before or after a meal, the usual advice is to take your doses after the same meal of the day each day.
    • If you forget to take a dose, take it as soon as you remember. If you do not remember until the following day, skip the forgotten dose. Do not take two doses at the same time to make up for a missed dose.

    Getting the most from your treatment

    • Tamsulosin can cause dizziness particularly when you first start taking it. This may affect your ability to drive. Make sure your reactions are normal before you drive or do things which would be dangerous if you were not fully alert.
    • Try to keep your regular appointments with your doctor. This is so your doctor can check on your progress. Your doctor may want to take your blood pressure from time to time, particularly when you first start the treatment.
    • You are advised not to drink alcohol while you are on tamsulosin. Alcohol increases the risk of side-effects from tamsulosin, such as feeling faint or dizzy.
    • Consider reducing or stopping the amount of caffeine you drink (commonly found in tea, coffee and cola). Caffeine can make your symptoms worse, so drinking less of these things may benefit you.
    • If you are a smoker, stopping smoking may significantly improve your symptoms. This is because nicotine irritates the bladder. You can ask your doctor for advice on quitting.
    • If you are having an operation or dental treatment, tell the person carrying out the treatment that you are taking tamsulosin. This is because your blood pressure may drop suddenly if you have an anaesthetic. If you are having cataract surgery, it is particularly important that you tell your surgeon you are on tamsulosin. This is because an eye problem known as ‘floppy iris syndrome’ has developed in some people and your doctor may advise you to stop taking tamsulosin for a short while.

    Can tamsulosin cause problems?

    Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with tamsulosin. You will find a full list in the manufacturer’s information leaflet supplied with your medicine. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome.

    Common tamsulosin side-effects (these affect less than 1 in 10 men) What can I do if I experience this?
    Feeling dizzy Do not drive and do not use tools or machines while affected
    Ejaculation problems If this becomes troublesome, speak with your doctor for advice

    If you experience any other symptoms which you think may be due to tamsulosin, speak with your doctor or pharmacist for further advice.

    How to store tamsulosin

    • Keep all medicines out of the reach and sight of children.
    • Store in a cool, dry place, away from direct heat and light.

    Important information about all medicines

    Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital. Take the container with you, even if it is empty.

    If you buy any medicines, always check with a pharmacist that they are safe to take alongside your prescribed medicines.

    This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

    Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

    If you have any questions about this medicine ask your pharmacist.

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