Roliten^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

G04BD07 (Tolterodine)

Active Substance

Tolterodine (Rec.INN registered by WHO)

Dosage Form

Roliten®

Film-coated tablets, 2 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white to almost white, round, biconvex.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium carboxymethyl starch (type A), colloidal silicon dioxide, magnesium stearate.

Shell composition: opadry white colorant (OY-S-58910) (hypromellose, titanium dioxide, macrogol 400, talc), purified water (evaporates during the manufacturing process).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Drug reducing the tone of the smooth muscles of the urinary tract

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of frequent urination and urinary incontinence

Pharmacological Action

An antagonist of m-cholinergic receptors localized in the bladder and salivary glands. Reduces the contractile function of the bladder and decreases salivation. Causes incomplete emptying of the bladder, increases the amount of residual urine and reduces detrusor pressure. The persistent therapeutic effect of tolterodine is achieved after 4 weeks.

Tolterodine and its active metabolite 5-hydroxymethyl are highly specific for muscarinic receptors and possess selectivity for bladder receptors (compared to salivary gland receptors).

Pharmacokinetics

Absorption

After oral administration, Tolterodine is rapidly absorbed from the gastrointestinal tract. C_max in serum is reached in 1-3 hours. The C_max value increases proportionally to the dose of tolterodine in the range from 1 to 4 mg.

The absolute bioavailability of tolterodine is 65% in individuals with reduced metabolism (lacking CYP2D6) and 17% in individuals with increased metabolism (most patients).

Food does not affect the exposure of unbound tolterodine and the active 5-hydroxymethyl metabolite in individuals with increased metabolism, although the level of tolterodine increases when taken with food.

Distribution

C_ss is achieved within 2 days. V_d of tolterodine is 113 L.

Metabolism

Tolterodine is mainly metabolized in the liver by the polymorphic enzyme CYP2D6 to form the pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to the formation of 5-carboxylic acid and its N-dealkylated metabolites.

In individuals with reduced metabolism (lacking CYP2D6), Tolterodine is not metabolized to the active 5-hydroxymethyl metabolite but undergoes dealkylation by CYP3A4 isoenzymes to form N-dealkylated tolterodine, which has no pharmacological activity.

Tolterodine and the 5-hydroxymethyl metabolite bind predominantly to orosomucoid; the unbound fractions are 3.7% and 36%, respectively.

Excretion

The systemic clearance of tolterodine in individuals with increased metabolism is about 30 L/h, and T_1/2 is 2-3 hours. The T_1/2 of the 5-hydroxymethyl metabolite is 3-4 hours.

After administration of ¹⁴C-tolterodine, approximately 77% of the radioactive label is excreted in the urine and 17% in the feces, with less than 1% excreted unchanged and about 4% as the active metabolite.

The carboxylated metabolite and its corresponding dealkylated metabolite account for about 51% and 29% of the amount excreted in the urine, respectively.

Pharmacokinetics in special clinical cases

Decreased clearance and prolonged T_1/2 (up to 10 hours) of tolterodine in individuals with reduced metabolism leads to an increase in its concentration (approximately 7-fold) against the background of undetectable concentrations of the 5-hydroxymethyl metabolite.

Consequently, the AUC value of tolterodine in individuals with reduced metabolism is close to the sum of the AUC values of tolterodine and its active 5-hydroxymethyl metabolite in patients with increased metabolism at the same dosing regimen.

Therefore, the safety, tolerability, and clinical effect of the drug are the same, regardless of the phenotype. The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases approximately 2-fold in patients with liver cirrhosis.

Indications

• Hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, imperative urges to urinate and/or urinary incontinence.

ICD codes

Dosage Regimen

Administer the drug orally. The recommended dose for adults is 2 mg twice daily.

Reduce the dose to 1 mg twice daily in patients with moderate hepatic impairment (Child-Pugh class B).

Reduce the dose to 1 mg twice daily in patients with severe renal impairment (creatinine clearance ≤30 mL/min) or those undergoing hemodialysis.

Initiate therapy at the lower dose of 1 mg twice daily for patients also receiving potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir).

Consider a dose reduction to 1 mg twice daily if adverse effects, such as dry mouth or dyspepsia, are not tolerated.

Swallow the tablet whole with a liquid. The tablets can be taken with or without food.

Re-evaluate the need for continued therapy after a treatment period of 6 months.

Do not use in children or adolescents under 18 years of age due to a lack of safety and efficacy data.

Adverse Reactions

Tolterodine may cause mild or moderately pronounced antimuscarinic effects, such as dry mouth, dyspepsia, and decreased tear fluid secretion.

Definition of categories of frequency of adverse effects (according to WHO): very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and < 1/100), rare (≥1/10 000 and <1/1000), very rare (<1/10 000), frequency unknown (frequency cannot be estimated from the available data).

Nervous system disorders: uncommon – headache, dizziness, drowsiness, nervousness, paresthesia; rare – consciousness disorders; frequency unknown – anxiety.

Digestive system disorders: uncommon – dyspepsia, constipation, abdominal pain, flatulence, vomiting; rare – gastroesophageal reflux.

Respiratory system disorders: frequency unknown – sinusitis.

Immune system disorders: rare – allergic reactions.

Eye disorders: vision disorders (including accommodation disorder), xerophthalmia (dryness of the sclera).

Urinary system disorders: frequency unknown – dysuria, urinary retention.

General disorders: uncommon – weakness, fatigue, weight increase; rare – chest pain, flushing.

Contraindications

• Hypersensitivity;
• Urinary retention;
• Angle-closure glaucoma (untreatable);
• Myasthenia gravis;
• Ulcerative colitis;
• Megacolon;
• Pregnancy;
• Lactation (breastfeeding);
• Childhood.

With caution: urinary tract obstruction, obstructive gastrointestinal lesions, neuropathy, irreducible hernia.

Use in Pregnancy and Lactation

The use of the drug Roliten^® is contraindicated during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use reliable methods of contraception during therapy with the drug Roliten^®.

Use in Hepatic Impairment

In case of hepatic impairment the dose is reduced to 1 mg 2 times/day.

Use in Renal Impairment

In case of renal impairment the dose is reduced to 1 mg 2 times/day.

Special Precautions

Before starting treatment, organic causes of frequent and imperative urges to urinate should be excluded.

Use in pediatrics

Roliten^® is not recommended for use in children, as the safety and efficacy of the drug in this category of patients have not been studied to date.

Effect on ability to drive vehicles and operate machinery

Since Roliten^® may cause accommodation disorders and reduce the speed of psychomotor reactions, the issue of the possibility of engaging in potentially hazardous activities should be decided only after assessing the individual patient’s response to the drug.

Overdose

Symptoms: the highest dose received by volunteers was 12.8 mg of tolterodine L-tartrate in a single dose. The most important symptoms noted were accommodation disorders and painful urge to urinate. Hallucinations, severe agitation, convulsions, respiratory failure, tachycardia, urinary retention, and pupil dilation are possible.

Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy – for pronounced central anticholinergic effects (including hallucinations) – physostigmine; for convulsions or severe agitation – benzodiazepines; for tachycardia – beta-blockers; for respiratory failure – artificial respiration; for urinary retention – catheterization; for pupil dilation – pilocarpine in the form of eye drops and/or moving the patient to a dark room.

Drug Interactions

When the drug Roliten^® is used concomitantly with other drugs that have anticholinergic properties, an enhancement of the therapeutic effect and adverse effects is possible.

When the drug Roliten^® is used concomitantly with m-cholinomimetics, its therapeutic effect may decrease.

When the drug Roliten^® is used concomitantly with metoclopramide and cisapride, a weakening of the effect of the latter is possible.

Pharmacokinetic interaction with other drugs that are metabolized by isoenzymes of the cytochrome P450 system (CYP2D6 or CYP3A4) or inhibit them is possible.

However, concomitant use of the drug Roliten^® with fluoxetine (a strong inhibitor of CYP2D6, which is metabolized to norfluoxetine, an inhibitor of CYP3A4) leads only to a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which does not cause a clinically significant interaction.

Concomitant treatment with strong inhibitors of CYP3A4, such as macrolide antibiotics (erythromycin and clarithromycin) or antifungal agents (ketoconazole, itraconazole and miconazole), should be avoided.

Clinical trials have established no interaction of the drug Roliten^® with warfarin or combined oral contraceptives (containing ethinylestradiol/levonorgestrel).

A clinical study using metabolic probes provided no indication that Tolterodine is capable of inhibiting the activity of CYP2D6, CYP2C19, CYP3A4 or CYP1A2.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.