Tioriva18 mcg

Tioriva is a long-acting anticholinergic (antimuscarinic) bronchodilator delivered by oral inhalation. Its uses are classified below by strength of evidence:

• Established/FDA-approved use — Chronic Obstructive Pulmonary Disease (COPD): Long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema, and for reducing COPD exacerbations.
• Established/FDA-approved use — Asthma (add-on therapy): Tioriva (mist inhaler formulation) is indicated as add-on maintenance treatment in patients with asthma who remain symptomatic despite use of inhaled corticosteroids, with or without additional long-acting beta-agonist (LABA) therapy. It is used in combination with, not as a substitute for, inhaled corticosteroid-based therapy.

Tioriva is not a rescue medication. It has a slow onset of action and is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., as rescue therapy for sudden shortness of breath.

Each formulation contains Tiotropium (as tiotropium bromide monohydrate) as the active ingredient. Marketed dosage forms and strengths include:

• Dry powder inhaler (capsule for inhalation, e.g., HandiHaler-type device): capsules containing Tiotropium equivalent to 18 mcg tiotropium, for oral inhalation only (not to be swallowed).
• Soft mist inhaler (metered spray, e.g., Respimat-type device): delivers 2.5 mcg of Tiotropium per actuation/puff; the recommended dose of 2 puffs delivers a total of 5 mcg.

Inactive ingredients vary by manufacturer and formulation and may include lactose monohydrate (in the dry-powder capsule form; contains trace milk protein) or water, benzalkonium chloride, and edetate disodium (in the soft mist spray form).

Tioriva is a long-acting, synthetic quaternary ammonium anticholinergic (antimuscarinic) compound structurally related to atropine and ipratropium, used as a once-daily inhaled bronchodilator for chronic respiratory disease.

Because it carries a permanent positive charge (quaternary ammonium structure), Tioriva is poorly absorbed across biological membranes, which limits its pharmacologic action largely to the lungs and airways and minimizes systemic anticholinergic effects relative to non-selective antimuscarinics such as atropine.

Tioriva is available as a dry powder for oral inhalation via a capsule-based handheld device, and as a solution delivered through a soft mist inhaler. It is used for long-term maintenance therapy and is not intended for as-needed or acute symptom relief.

Anticholinergic (antimuscarinic) bronchodilator; Tioriva belongs to the long-acting muscarinic antagonist (LAMA) class of respiratory drugs.

Mechanism of Action

Tiotropium is a long-acting muscarinic receptor antagonist that binds with similar affinity to M1, M2, and M3 muscarinic receptor subtypes but dissociates much more slowly from M3 and M1 receptors than from M2 receptors. Because bronchial smooth muscle tone is mediated mainly by M3 receptors, this kinetic selectivity produces sustained inhibition of acetylcholine-induced bronchoconstriction, resulting in prolonged bronchodilation with once-daily dosing. Reduced mucus gland secretion also occurs due to M3 receptor blockade.

Pharmacokinetics

After inhalation, Tiotropium is absorbed from the lung, with absolute bioavailability of approximately 19–33% depending on the device. Peak plasma concentrations occur within 5–7 minutes (soft mist inhaler) after dosing. Plasma protein binding is low (72%), and steady state is reached after about 2–3 weeks of once-daily dosing. Tiotropium undergoes minimal hepatic metabolism; the majority of the absorbed dose is excreted unchanged in the urine, with a terminal half-life of approximately 5–6 days (capsule form) to 25 hours (soft mist inhaler), consistent with once-daily maintenance dosing. Onset of clinically meaningful bronchodilation begins within 30 minutes, with peak effect at 3 hours, and effects are sustained over 24 hours.

Tioriva is administered exclusively by oral inhalation using the specific device supplied with the product (a capsule-based handheld inhaler or a soft mist inhaler); the two device/formulation types are not interchangeable, and capsules intended for the dry powder device must never be swallowed. Patients should be trained in correct inhaler technique by a healthcare professional or pharmacist, as inadequate technique substantially reduces lung deposition and clinical effect. Care should be taken to avoid spraying or allowing the powder or mist to contact the eyes.

Clinically significant, well-verified interactions with Tioriva include:

• Other anticholinergic (antimuscarinic) medicines (e.g., ipratropium, other LAMAs, certain antihistamines, tricyclic antidepressants, some antipsychotics, and antispasmodics): concurrent use may produce additive anticholinergic effects such as dry mouth, constipation, and urinary retention. Concomitant use of Tioriva with another inhaled anticholinergic agent is not recommended.
• Long-acting beta-agonists (LABA) and inhaled corticosteroids: commonly co-administered with Tioriva for complementary bronchodilator/anti-inflammatory effect in COPD and asthma; no clinically important pharmacokinetic interaction is established, and combination is a recognized part of guideline-directed therapy.

Because systemic absorption of Tioriva is limited, clinically significant interactions with systemically-acting drugs metabolized via cytochrome P450 pathways have not been well established.

The most commonly reported adverse effects of Tioriva are related to its local and systemic anticholinergic action:

• Very common/common: dry mouth (the most frequently reported effect), upper respiratory tract infection symptoms, sinusitis, and pharyngitis.
• Common: constipation, cough, dizziness, and urinary tract infection.
• Uncommon: urinary retention or difficulty voiding (particularly in patients with pre-existing bladder outlet obstruction or prostatic hyperplasia), blurred vision, tachycardia, and epistaxis.
• Rare but serious: paradoxical bronchospasm (a sudden worsening of wheeze/breathlessness immediately after use — treatment should be discontinued and alternative therapy sought if this occurs), acute angle-closure glaucoma or worsening of narrow-angle glaucoma from ocular contact, angioedema and other hypersensitivity reactions (see Contraindications), and, in patients with underlying cardiac disease, cardiac arrhythmias.

Pregnancy: There are no adequate and well-controlled studies of Tioriva in pregnant women. Because systemic absorption is limited, fetal systemic exposure is expected to be low, but Tioriva should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus; a physician should be consulted before use in pregnancy.

Lactation: It is not known whether Tioriva is excreted in human breast milk, although it has been detected in the milk of lactating animals. A decision should be made to discontinue breastfeeding or discontinue Tioriva, taking into account the importance of the drug to the mother; a physician or lactation specialist should be consulted before use while breastfeeding.

• Not for acute symptoms: Tioriva is a maintenance bronchodilator with a slow onset of action and must not be used for the initial treatment of acute episodes of bronchospasm or as a rescue inhaler; a fast-acting rescue bronchodilator should be available for acute symptoms.
• Paradoxical bronchospasm: As with other inhaled bronchodilators, Tioriva can cause paradoxical bronchospasm that may be life-threatening. If this occurs, Tioriva should be discontinued immediately and alternative therapy instituted.
• Ocular effects: Avoid spraying or allowing Tioriva powder/mist to contact the eyes; direct ocular exposure can precipitate or worsen narrow-angle (angle-closure) glaucoma, causing eye pain, blurred vision, visual halos, and conjunctival or corneal redness. Patients with pre-existing narrow-angle glaucoma should be counseled to protect their eyes and to seek immediate ophthalmologic advice if any such symptoms develop.
• Urinary retention: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia, since anticholinergic effects may worsen urinary retention.
• Renal impairment: Patients with moderate-to-severe renal impairment have increased systemic exposure to Tioriva and should be monitored closely for anticholinergic adverse effects.
• Immediate hypersensitivity reactions: Angioedema, including of the pharynx and larynx, may occur, sometimes after the first dose; if this occurs, Tioriva should be discontinued immediately and alternative treatment instituted.
• Not a substitute for inhaled corticosteroids in asthma: when used as add-on asthma therapy, Tioriva does not replace anti-inflammatory therapy and should be used together with, not instead of, the patient's inhaled corticosteroid-based regimen.

Because systemic absorption of Tioriva is limited after inhaled use, severe systemic toxicity from accidental overdose is uncommon; however, high doses may produce exaggerated anticholinergic effects such as dry mouth, blurred vision, tachycardia, urinary retention, and constipation. If overdose is suspected, particularly with accidental ingestion of the inhalation solution or multiple capsules, or if severe or unusual symptoms occur, seek immediate medical attention or contact a poison control center; treatment is supportive and symptomatic, as there is no specific antidote for Tioriva.

Store at room temperature (below 30°C), away from light and moisture. Keep capsules in the blister until immediately before use. Do not freeze the soft mist inhaler cartridge. Keep out of reach of children.

• Renal impairment: Systemic exposure to Tioriva is increased in moderate-to-severe renal impairment; monitor closely for anticholinergic side effects (see Precautions and Warnings).
• Hepatic impairment: No dose adjustment is considered necessary, as Tioriva undergoes minimal hepatic metabolism.
• Elderly: No age-related dose adjustment is required, but elderly patients may be more susceptible to anticholinergic effects such as urinary retention, constipation, and glaucoma exacerbation.
• Pediatric: See Pediatric Uses for age-specific approved indications and dosing.

Tioriva is intended for long-term, regular, once-daily maintenance therapy in COPD and, where used, as asthma add-on therapy, for as long as the prescribing physician determines it is needed to control symptoms and reduce exacerbations. It is not intended to be stopped and started intermittently for symptom relief, and effectiveness depends on consistent daily use. Any decision to stop or change Tioriva therapy should be made by the prescribing physician, generally based on ongoing symptom control and periodic reassessment.

Tiotropium belongs to the anticholinergic (antimuscarinic) bronchodilator class, specifically the long-acting muscarinic antagonist (LAMA) subclass; related classes include short-acting muscarinic antagonists (e.g., ipratropium) and beta-2 agonist bronchodilators, with which Tiotropium is often used concurrently.

Tiotropium works by binding to muscarinic acetylcholine receptors (M1, M2, M3) in the airway, with prolonged (kinetically selective) dissociation from M3 and M1 receptor subtypes relative to M2. Because bronchoconstriction is chiefly mediated through M3 receptors on airway smooth muscle, this slow dissociation produces sustained, once-daily inhibition of vagally-mediated bronchoconstriction and mucus secretion, resulting in prolonged bronchodilation. Because Tiotropium is a quaternary ammonium compound with poor lipid solubility, its action is largely confined to the lungs, with minimal systemic anticholinergic effect at recommended doses.

Use of Tioriva in children is indication- and formulation-specific:

• COPD: COPD is a disease of adults; safety and efficacy of Tioriva for COPD have not been established in children, and it is not indicated for pediatric COPD.
• Asthma, add-on maintenance therapy (soft mist inhaler only): Tioriva soft mist inhaler is approved as add-on maintenance treatment for asthma in children 6 years of age and older who remain symptomatic on inhaled corticosteroid-based therapy, at the same once-daily 2-inhalation dose used in adults.
• Under 6 years of age: Safety and efficacy of Tioriva have not been established in children younger than 6 years for any indication.
• Dry powder capsule inhaler: This device/formulation is approved for COPD in adults only; it is not indicated for pediatric asthma.