Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Posology 

One capsule a day after breakfast or the first meal of the day. The capsule is swallowed whole with a glass of water while standing or sitting (not lying down). The capsule should not be broken or pulled apart as this may have an effect on the release of the long-acting active ingredient.

Hepatic/renal impairment

No dose adjustment is warranted in renal impairment. No dose adjustment is warranted in patients with mild to moderate hepatic insufficiency (see also 4.3 Contraindications).

Paediatric population

The safety and efficacy of tamsulosin in children < 18 years have not been established. Currently available data are described in section 5.1.

Method of administration

Oral use.

The capsule is swallowed whole, without crushing or chewing, because otherwise the controlled release of the active ingredient would be affected.

As with other α1-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin as a result of which, rarely, syncope can occur. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Before therapy with tamsulosin is initiated, the patient should be examined in order to exclude the presence of other conditions, which can cause the same symptoms as benign prostatic hyperplasia.

Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed before treatment and at regular intervals afterwards.

The treatment of patients with severe renal impairment (creatinine clearance of < 10 ml/min) should be approached with caution, as these patients have not been studied.

Angio-oedema has been rarely reported after the use of tamsulosin. Treatment should be discontinued immediately, patient should be monitored until disappearance of the oedema, and tamsulosin should not be readministered.

The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin.

IFIS may increase the risk of eye complications during and after the operation. The initiation of therapy with tamsulosin in patients for whom cataract surgery is scheduled is not recommended.

Discontinuing tamsulosin 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not yet been established. 

IFIS has also been reported in patients who had discontinued tamsulosin for a longer period prior to cataract surgery.

During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with tamsulosin in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Tamsulosin hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype. Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4 (See section 4.5)

 Excipient

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

Interaction studies have only been performed in adults.

No interactions have been seen when tamsulosin was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant cimetidine brings about a rise in plasma levels of tamsulosin, whereas furosemide a fall, but as levels remain within the normal range posology need not be adjusted.

In vitro, neither diazepam nor propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin and warfarin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide and chlormadinone.

Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin.

Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 may lead to increased exposure to tamsulosin hydrochloride. Concomitant administration with ketoconazole (a known strong CYP3A4 inhibitor) resulted in an increase in AUC and C_max of tamsulosin hydrochloride by a factor of 2.8 and 2.2, respectively.

Tamsulosin hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype. Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4.

Concomitant administration of tamsulosin hydrochloride with paroxetine, a strong inhibitor of CYP2D6, resulted in a Cmax and AUC of tamsulosin that had increased by a factor of 1.3 and 1.6, respectively, but these increases are not considered clinically relevant.

Concurrent administration of other α1-adrenoceptor antagonists could lead to hypotensive effects.

Tamsulosin is intended for males only.

Ejaculation disorders have been observed in short- and long-term clinical studies with tamsulosin. Events of ejaculation disorder, retrograde ejaculation and ejaculation failure have been reported in the post authorization phase.

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be aware of the fact that dizziness can occur.

a) Summary of safety

Not Applicable

b) Tabulated adverse reactions

The frequency of adverse reactions of tamsulosin listed below is defined using the following convention: Common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

c)  Description of selected adverse events:

During cataract surgery a small pupil situation, known as Intraoperative Floppy Iris Syndrome (IFIS), has been associated with therapy of tamsulosin during post-marketing surveillance

d)  Pediatric use:

Not applicable

e)  Other special population:

Renal Patients:

The treatment of severely renally impaired patients (creatinine clearance of

 < 10 ml/min) should be approached with caution as these patients have-not been studied. IFIS: The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin.

IFIS may lead to increased procedural complications during the operation. The initiation of therapy with tamsulosin in patients for whom cataract surgery is scheduled is not recommended.

To Report side effects

 Saudi Arabia 

National Pharmacovigilance Center (NPC)

SFDA Call center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/  

 Other GCC States

Please contact the relevant competent authority.

Symptoms 

Acute overdose with 5 mg tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed, which were treated with fluid replacement and the patient could be discharged the same day. 

Treatment 

In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders and, when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied.

Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins. 

Measures, such as emesis, can be taken to impede absorption if large quantities of the medicinal product are involved, gastric lavage may be performed and activated charcoal and an osmotic laxative, such as sodium sulphate, may be given.

Pharmacotherapeutic group: α1A adrenoreceptor antagonist. ATC code: G04CA02  

Mechanism of action 

Tamsulosin binds selectively and competitively to postsynaptic α1A adrenoreceptors, which convey smooth muscle contraction, thereby relaxing prostatic and urethral smooth muscle. please contact the relevant competent authority.

Pharmacodynamic effects

Tamsulosin increases the maximum urinary flow rate by relaxing prostatic and urethral smooth muscle, thus relieving obstruction.

The medicinal product also improves the irritative and obstructive symptoms in which the contraction of smooth muscle in the lower urinary tract plays an important role.

Alpha-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin in normotensive patients.

The medicinal product's effect on storage and voiding symptoms are also maintained during long-term therapy, as a result of which the need for surgical treatment is significantly postponed.

Paediatric population

A double-blind, randomized, placebo-controlled, dose ranging study was performed in children with neuropathic bladder. A total of 161 children (with an age of 2 to 16 years) were randomized and treated at 1 of 3 dose levels of tamsulosin (low 0.001 to 0.002 mg/kg) medium [0.002 to 0.004 mg/kg], and high [0.004 to 0.008 mg/kg]), or placebo. The primary endpoint was number of patients who decreased their detrusor leak point pressure (LPP) to 40> cm H2O based upon two evaluations on the same day. Secondary endpoints were:

Actual and percent change from baseline in detrusor leak point pressure, improvement or stabilization of hydronephrosis and hydroureter and change in urine volumes obtained by catheterisation and number of times wet at time of catheterisation as recorded in catheterisation diaries. No statistically significant difference was found between the placebo group and any of the 3 tamsulosin dose groups for either the primary or any secondary endpoints. No dose response was observed for any dose level.

Absorption

Tamsulosin is absorbed from the intestinal tract and its bioavailability is almost complete. The absorption of tamsulosin decreases if the product is administered shortly after the meal. The uniformity of absorption may be supported via using tamsulosin capsules always after the same daily meal.

Kinetics of tamsulosin is linear.

After a single dose of tamsulosin taken after a full meal, the peak plasma levels are achieved at approximately 6 hours. The steady state is reached by day five of multiple dosing, when C_max in patients is about two thirds higher than that reached after a single dose. Although this has been demonstrated only in the elderly, the same result would also be expected in younger patients.

There are huge inter-patient variations in plasma levels of tamsulosin, both after single as well as multiple dosing.

Distribution

In humans, approximately 99% of tamsulosin is bound to plasma proteins and its distribution volume is small (approximately 0.2 l/kg).

Biotransformation

Tamsulosin has a low first pass metabolic effect. The majority of tamsulosin is present in plasma in an unchanged form. Tamsulosin is metabolized in the liver. In studies on rats, an induction of microsomal liver enzymes induced by tamsulosin has not been practically observed. In vitro results suggest that CYP3A4 and also CYP2D6 are involved in metabolism, with possible minor contributions to tamsulosin hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride (see sections 4.4 and 4.5).

Dosage adjustment is not necessary in mild hepatic insufficiency.

The metabolites are not as effective and toxic as the active medicinal product itself.

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine; approximately 9% of the dose given is released in an unchanged form. The elimination half-life of tamsulosin in patients is approximately 10 hours (when taken after a meal) and 13 hours in the steady state.

In case of renal affections, no reduction of tamsulosin doses is substantiated.

Toxicity after a single dose and multiple dosing has been investigated in mice, rats and dogs. Reproductive toxicity has also been investigated in rats, carcinogenicity in mice and rats, and genotoxicity in vivo and in vitro. The common toxicity profile found with large doses of tamsulosin is equivalent to the pharmacological effect associated with alpha adrenergic antagonists. Changes in ECG readings were found with very large doses in dogs. This is not, however, assumed to be of any clinical significance. Tamsulosin has not been found to have any significant genotoxic properties.

Greater proliferative changes in the mammary glands of female rats and mice have been discovered on exposure to tamsulosin. These findings, which are probably indirectly linked to hyperprolactinemia and only occur as a result of large doses having been taken, are considered clinically insignificant .

Granulating Solution

Polysorbate 80

Methacrylic Acid Copolymer Dispersion (Eudragit L30D 55)

Triacetin (Emprove exp)

Sodium Lauryl Sulfate (Texapon K 12 P PH)

Purified Water 

Dry Mix 

Microcrystalline Cellulose (Avicel PH 101)

Polymer Coating Solution

Methacrylic Acid Copolymer Dispersion (Eudragit L30D 55)

Triacetin (Emprove exp)

Purified Water

Lubrication

Calcium Stearate (VG-EP/Ligamed CPR-2-V)

Capsule Cap

FD & C Blue 2 (E 132)

Iron oxide black (E 172)

Iron oxide red (E 172)

Iron oxide yellow (E 172)

Titanium dioxide (E 171)

Gelatin

Water

Sodium lauryl sulfate

Capsule Body

Iron oxide red (E 172)

Iron oxide yellow (E 172)

Titanium dioxide (E 171)

Gelatin

Water

Sodium lauryl sulfate

Not applicable

Store below 30^OC.

PVC/PE/PVdC – Aluminum blister packs containing 30 Capsules

No special requirements.