4.1. Therapeutic indications

Treatment of moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with benign prostatic hyperplasia (BPH) in men who are not adequately responding to treatment with monotherapy.

4.2. Posology and method of administration

Adult males, including older people

One Vesomni tablet (6 mg/0.4 mg) once daily taken orally with or without food. The maximum daily dose is one Vesomni tablet (6 mg/0.4 mg).

The tablet must be swallowed whole, intact without biting or chewing. Do not crush the tablet.

Patients with renal impairment

The effect of renal impairment on the pharmacokinetics of Vesomni has not been studied. However, the effect on the pharmacokinetics of the individual active substances is well known (see section 5.2). Vesomni can be used in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) should be treated with caution and the maximum daily dose in these patients is one Vesomni tablet (6 mg/0.4 mg) (see section 4.4).

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of Vesomni has not been studied. However, the effect on the pharmacokinetics of the individual active substances is well known (see section 5.2). Vesomni can be used in patients with mild hepatic impairment (Child-Pugh score ≤ 7). Patients with moderate hepatic impairment (Child-Pugh score 7-9) should be treated with caution and the maximum daily dose in these patients is one Vesomni tablet (6 mg/0.4 mg). In patients with severe hepatic impairment (Child-Pugh score > 9), the use of Vesomni is contraindicated (see section 4.3).

Moderate and strong inhibitors of cytochrome P450 3A4

The maximum daily dose of Vesomni should be limited to one tablet (6 mg/0.4 mg). Vesomni should be used with caution in patients treated simultaneously with moderate or strong CYP3A4 inhibitors, e.g. verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole (see section 4.5).

Paediatric population

There is no relevant indication for use of Vesomni in children and adolescents.

4.3. Contraindications

- Patients with hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1,

- Patients undergoing haemodialysis (see section 5.2),

- Patients with severe hepatic impairment (see section 5.2),

- Patients with severe renal impairment who are also treated with a strong cytochrome P450 (CYP) 3A4 inhibitor, e.g., ketoconazole (see section 4.5),

- Patients with moderate hepatic impairment who are also treated with a strong CYP3A4 inhibitor, e.g., ketoconazole (see section 4.5),

- Patients with severe gastrointestinal conditions (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and patients at risk for these conditions,

- Patients with a history of orthostatic hypotension.

4.4. Special warnings and precautions for use

Vesomni should be used with caution in patients with:

- severe renal impairment,

- risk of urinary retention,

- gastrointestinal obstructive disorders,

- risk of decreased gastrointestinal motility,

- hiatus hernia/gastroesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis,

- autonomic neuropathy.

The patient should be examined in order to exclude the presence of other conditions, which can cause similar symptoms to benign prostatic hyperplasia.

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Vesomni is initiated. If a urinary tract infection is present, appropriate antibacterial therapy should be started.

QT prolongation and Torsade de Pointes have been observed in patients with risk factors, such as pre-existing long QT syndrome and hypokalaemia, who are treated with solifenacin succinate.

Angioedema with airway obstruction has been reported in some patients on solifenacin succinate and tamsulosin. If angioedema occurs, Vesomni should be discontinued and not restarted. Appropriate therapy and/or measures should be taken.

Anaphylactic reaction has been reported in some patients treated with solifenacin succinate. In patients who develop anaphylactic reactions, Vesomni should be discontinued and appropriate therapy and/or measures should be taken.

As with other alpha1-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. Patients starting treatment with Vesomni should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have disappeared.

The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of eye complications during and after the operation. Therefore, the initiation of therapy with Vesomni in patients for whom cataract or glaucoma surgery is scheduled is not recommended. Discontinuing treatment with Vesomni 1-2 weeks prior to cataract or glaucoma surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not been established. During pre-operative assessment, surgeons and ophthalmic teams should consider whether patients scheduled for cataract or glaucoma surgery are being or have been treated with Vesomni in order to ensure that appropriate measures will be in place to manage IFIS during surgery.

Vesomni should be used with caution in combination with moderate and strong inhibitors of CYP3A4 (see section 4.5) and it should not be used in combination with strong inhibitors of CYP3A4, e.g., ketoconazole, in patients who are of the CYP2D6 poor metaboliser phenotype or who are using strong inhibitors of CYP2D6, e.g., paroxetine.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant medication with any medicinal products with anticholinergic properties may result in more pronounced therapeutic effects and undesirable effects. An interval of approximately one week should be allowed after stopping treatment with Vesomni, before commencing any anticholinergic therapy. The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists.

Interactions with CYP3A4 and CYP2D6 inhibitors

Concomitant administration of solifenacin with ketoconazole (a strong inhibitor of CYP3A4) (200 mg/day) resulted in a 1.4- and 2.0-fold increase in Cmax and area under the curve (AUC) of solifenacin, while ketoconazole at a dose of 400 mg/day resulted in a 1.5- and 2.8-fold increase in Cmax and AUC of solifenacin.

Concomitant administration of tamsulosin with ketoconazole at a dose of 400 mg/day resulted in a 2.2- and 2.8-fold increase in Cmax and AUC of tamsulosin, respectively.

Since concomitant administration with strong inhibitors of CYP3A4, such as ketoconazole, ritonavir, nelfinavir and itraconazole may lead to increased exposure to both solifenacin and tamsulosin, Vesomni should be used with caution in combination with strong CYP3A4 inhibitors.

Vesomni should not be given together with strong CYP3A4 inhibitors in patients who are also CYP2D6 poor metaboliser phenotype or who are already using strong CYP2D6 inhibitors.

Concomitant administration of Vesomni with verapamil (a moderate CYP3A4 inhibitor) resulted in an approximately 2.2-fold increase in Cmax and AUC of tamsulosin and an approximately 1.6-fold increase in the Cmax and AUC of solifenacin. Vesomni should be used with caution in combination with moderate inhibitors of CYP3A4.

Concomitant administration of tamsulosin with the weak CYP3A4 inhibitor cimetidine (400 mg every 6 hours) resulted in a 1.44-fold increase in the AUC of tamsulosin, while Cmax was not significantly changed. Vesomni can be used with weak CYP3A4 inhibitors.

Concomitant administration of tamsulosin with the strong CYP2D6 inhibitor paroxetine (20 mg/day) resulted in an increase in Cmax and AUC of tamsulosin by 1.3- and 1.6-fold, respectively. Vesomni can be used with CYP2D6 inhibitors.

The effect of enzyme induction on the pharmacokinetics of solifenacin and tamsulosin has not been studied. Since solifenacin and tamsulosin are metabolised by CYP3A4, pharmacokinetic interactions are possible with CYP3A4 inducers (e.g., rifampicin) which may decrease the plasma concentration of solifenacin and tamsulosin.

Other Interactions

The following statements reflect the information available on the individual active substances.

Solifenacin

- Solifenacin can reduce the effect of medicinal products that stimulate the motility of the gastrointestinal tract, such as metoclopramide and cisapride.

- In vitro studies with solifenacin have demonstrated that at therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4. Therefore, no interactions are expected between solifenacin and drugs metabolised by these CYP enzymes.

- Intake of solifenacin did not alter the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time.

- Intake of solifenacin showed no effect on the pharmacokinetics of digoxin.

Tamsulosin

- Co-administration with other alpha1-adrenoceptor antagonists could lead to hypotensive effects.

- In vitro, the free fraction of tamsulosin in human plasma was not changed by diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin or warfarin. Tamsulosin does not change the free fraction of diazepam, propranolol, trichlormethiazide or chlormadinone. Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin.

- Co-administration with furosemide causes a fall in plasma levels of tamsulosin, but as levels remain within the normal range, concurrent use is acceptable.

- In vitro studies with tamsulosin have demonstrated that at therapeutic concentrations, tamsulosin does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. Therefore, no interactions are expected between tamsulosin and drugs metabolised by these CYP enzymes.

- No interactions have been seen when tamsulosin was given concomitantly with atenolol, enalapril, or theophylline.

4.6. Fertility, pregnancy and lactation

Fertility

The effect of Vesomni on fertility has not been established. Animal studies with solifenacin or tamsulosin do not indicate harmful effects on fertility and early embryonic development (see section 5.3).

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.

Pregnancy and lactation

Vesomni is not indicated for use in women.

4.7. Effects on ability to drive and use machines

No studies on the effects of Vesomni on the ability to drive or use machines have been performed. However, patients should be informed about the possible occurrence of dizziness, blurred vision, fatigue and uncommonly, somnolence, which may negatively affect the ability to drive or use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Vesomni may cause anticholinergic undesirable effects of, in general, mild to moderate severity. The most frequently reported adverse reactions during the clinical studies performed for the development of Vesomni were dry mouth (9.5%), followed by constipation (3.2%) and dyspepsia (including abdominal pain; 2.4%). Other common undesirable effects are dizziness (including vertigo; 1.4%), vision blurred (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation; 1.5%). Acute urinary retention (0.3%, uncommon) is the most serious adverse drug reaction that has been observed during treatment with Vesomni in clinical studies.

Tabulated list of adverse reactions

In the table below the 'Vesomni frequency' column reflects adverse drug reactions that have been observed during the double-blind clinical studies performed for the development of Vesomni (based on reports of treatment-related adverse events, which have been reported by at least two patients and occurred with a frequency higher than for placebo in the double-blind studies).

The columns 'solifenacin frequency' and 'tamsulosin frequency' reflect adverse drug reactions (ADRs) previously reported with one of the individual components (as presented in the Summary of Product Characteristics (SmPCs) of solifenacin 5 and 10 mg and tamsulosin 0.4 mg respectively) that may also occur when receiving Vesomni (some of these have not been observed during the clinical development program of Vesomni).

The frequency of adverse reactions is defined as follows: very common (≥1/10); 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).

System Organ Class (SOC) /Preferred Term (PT)

ADR frequency observed during development of Vesomni

ADR frequency observed with the individual substances

Solifenacin 5 mg and 10 mg#

Tamsulosin 0.4 mg#

Infections and infestations

Urinary tract infection

Uncommon

Cystitis

Uncommon

Immune system disorders

Anaphylactic reaction

Not known*

Metabolism and nutrition disorders

Decreased appetite

Not known*

Hyperkalaemia

Not known*

Psychiatric disorders

Hallucination

Very rare*

Confusional state

Very rare*

Delirium

Not known*

Nervous system disorders

Dizziness

Common

Rare*

Common

Somnolence

Uncommon

Dysgeusia

Uncommon

Headache

Rare*

Uncommon

Syncope

Rare

Eye disorders

Vision blurred

Common

Common

Not known*

Intraoperative Floppy Iris Syndrome (IFIS)

Not known**

Dry eyes

Uncommon

Glaucoma

Not known*

Visual impairment

Not known*

Cardiac disorders

Palpitations

Not known*

Uncommon

Torsade de Pointes

Not known*

Electrocardiogram QT prolongation

Not known*

Atrial fibrillation

Not known*

Not known*

Arrhythmia

Not known*

Tachycardia

Not known*

Not known*

Vascular disorders

Orthostatic hypotension

Uncommon

Respiratory, thoracic and mediastinal disorders

Rhinitis

Uncommon

Nasal dryness

Uncommon

Dyspnoea

Not known*

Dysphonia

Not known*

Epistaxis

Not known*

Gastrointestinal disorders

Dry mouth

Common

Very common

Dyspepsia

Common

Common

Constipation

Common

Common

Uncommon

Nausea

Common

Uncommon

Abdominal pain

Common

Gastro-oesophageal reflux disease

Uncommon

Diarrhea

Uncommon

Dry throat

Uncommon

Vomiting

Rare*

Uncommon

Colonic obstruction

Rare

Faecal impaction

Rare

Ileus

Not known*

Abdominal discomfort

Not known*

Hepatobiliary disorders

Liver disorder

Not known*

Liver function test abnormal

Not known*

Skin and subcutaneous tissue disorders

Pruritus

Uncommon

Rare*

Uncommon

Dry skin

Uncommon

Rash

Rare*

Uncommon

Urticaria

Very rare*

Uncommon

Angioedema

Very rare*

Rare

Stevens-Johnson syndrome

Very rare

Erythema multiforme

Very rare*

Not known*

Exfoliative dermatitis

Not known*

Not known*

Musculoskeletal and connective tissue disorders

Muscular weakness

Not known*

Renal and urinary disorders

Urinary retention***

Uncommon

Rare

Difficulty in micturition

Uncommon

Renal impairment

Not known*

Reproductive system and breast disorders

Ejaculation disorders including retrograde ejaculation and ejaculation failure

Common

Common

Priapism

Very rare

General disorders and administration site conditions

Fatigue

Common

Uncommon

Peripheral oedema

Uncommon

Asthenia

Uncommon

#: The ADRs from solifenacin and tamsulosin included in this table are the ADRs listed in the summary of product characteristics of both products.

*: from post-marketing reporting. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of solifenacin or tamsulosin and their causation cannot be reliably determined.

**: from post-marketing reporting, observed during cataract and glaucoma surgery.

***: see section 4.4 Special warnings and precautions for use.

Long –term safety of Vesomni

The profile of undesirable effects seen with treatment up to 1 year was similar to that observed in the 12-week studies. The product is well-tolerated and no specific adverse reactions have been associated with long-term use.

Description of selected adverse reactions

For urinary retention see section 4.4 Special warnings and precautions for use.

Older people

The therapeutic indication of Vesomni, moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with BPH, is a disease affecting elderly men. The clinical development of Vesomni has been performed in patients 45 to 91 years of age, with an average age of 65 years. Adverse reactions in the elderly population were similar to the younger population.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Overdosage with the combination of solifenacin and tamsulosin can potentially result in severe anticholinergic effects plus acute hypotension. The highest dose taken accidentally during a clinical study corresponded to 126 mg of solifenacin succinate and 5.6 mg of tamsulosin hydrochloride. This dose was well-tolerated, with mild dry mouth for 16 days as the only reported adverse event.

Treatment

In the event of overdose with solifenacin and tamsulosin, the patient should be treated with activated charcoal. Gastric lavage is useful if performed within 1 hour, but vomiting should not be induced.

As for other anticholinergics, symptoms of overdose due to the solifenacin component can be treated as follows:

- Severe central anticholinergic effects such as hallucinations or pronounced excitation: treat with physostigmine or carbachol.

- Convulsions or pronounced excitation: treat with benzodiazepines.

- Respiratory insufficiency: treat with artificial respiration.

- Tachycardia: treat symptomatically if needed. Beta-blockers should be used with caution, since the concomitant overdose with tamsulosin could potentially induce severe hypotension.

- Urinary retention: treat with catheterisation.

As with other antimuscarinics, in case of overdosing, specific attention should be paid to patients with a known risk for QT-prolongation (i.e., hypokalaemia, bradycardia and concurrent administration of medicinal products known to prolong QT-interval) and relevant pre-existing cardiac diseases (i.e., myocardial ischaemia, arrhythmia, congestive heart failure).

Acute hypotension, which can occur after overdosage due to the tamsulosin component, should be treated symptomatically. Hemodialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.