Grasulan

Posology

One capsule daily after breakfast or after the first daily meal.

Hepatic/renal impairment

No dose adjustment is warranted in renal impairment.

No dose adjustment is warranted in patients with mild to moderate hepatic insufficiency.

Paediatric population

The safety and efficacy of Grasulan hydrochloride in children < 18 years have not been established.

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.

- History of orthostatic hypotension.

- Severe hepatic insufficiency.

- Micturition syncope history

As with other α₁-adrenoceptors antagonists, a reduction in blood pressure can occur in individual cases during treatment with Grasulan hydrochloride 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 Grasulan hydrochloride 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.

Angioedema has been rarely reported after the use of Grasulan. In case of angioedema, treatment should be discontinued immediately, the patient should be monitored until disappearance of the oedema, and Grasulan should not be re-administered.

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 Grasulan hydrochloride. IFIS may increase the risk of eye complications during and after the operation.

Discontinuing Grasulan hydrochloride 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 Grasulan for a longer period prior to cataract surgery.

The initiation of therapy with Grasulan hydrochloride in patients for whom cataract surgery is scheduled is not recommended. During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Grasulan in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Grasulan hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype.

Grasulan hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4.

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.

Tabulated list of adverse reactions

The frequency of adverse reactions of Grasulan 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).

* Observed post-marketing.

Post-marketing experience: In addition to the adverse events listed above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported in association with Grasulan hydrochloride use. Because these spontaneously reported events are from the worldwide post marketing experience, the frequency of events and the role of Grasulan in their causation cannot be reliably determined.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

Overdosage with Grasulan hydrochloride can potentially result in severe hypotensive effects. Severe hypotensive effects have been observed at different levels of overdosing.

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 Grasulan is very highly bound to plasma proteins.

Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Pharmacotherapeutic category: Adrenergic α₁-receptors antagonist.

ATC: G04CA02.

The product is designed exclusively for the treatment of diseases of the prostate.

Mechanism of action

Grasulan binds selectively and competitively to post-synaptic α₁-adrenoreceptors, prevailingly their subtypes designated α_1A and α_1D. Thus relaxation of smooth muscles of the prostate and urethra is achieved, which leads to a reduction of tonus and an improvement of the urinary flow.

Pharmacodynamic effects

Grasulan increases the maximum urinary flow. Due to relaxation of smooth muscles in the prostate and the urethra, obstruction is decreased, which leads to alleviation of voiding symptoms.

Grasulan also alleviates the storage symptoms in the development of which also the instability of the urinary bladder is involved at a significant extent. The effects on symptoms of filling and depletion of the urinary bladder persist during long-term treatment. The necessity of surgical treatment or catheterization is significantly delayed owing to these effects.

α₁-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with Grasulan in normotensive patients.

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 Grasulan (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 Grasulan dose groups for either the primary or any secondary endpoints. No dose response was observed for any dose level.

Absorption

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

Kinetics of Grasulan is linear.

After a single dose of Grasulan 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 Grasulan, both after single as well as multiple dosing.

Distribution

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

Biotransformation

Grasulan has a low first pass metabolic effect. The majority of Grasulan is present in plasma in an unchanged form. Grasulan is metabolized in the liver.

In studies on rats, an induction of microsomal liver enzymes induced by Grasulan has not been practically observed.

In vitro results suggest that CYP3A4 and also CYP2D6 are involved in metabolism, with possible minor contributions to Grasulan hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to Grasulan hydrochloride.

Dosage adjustment is not necessary in mild hepatic insufficiency.

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

Elimination

Grasulan 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 Grasulan 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 Grasulan 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 with large doses of Grasulan 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. Grasulan has not been found to have any significant genotoxic properties.

An increased incidence of proliferative alterations in the mammary glands of rat and mice females has been found. These findings, which are probably indirectly linked to hyperprolactinaemia and only occur as a result of large doses having been taken, are considered clinically insignificant.

Not applicable.

No special requirements.