Tiotropium
JFDA label: Spiriva Respimat
Mechanism of Action
Competitively and reversibly inhibits the action of acetylcholine at type 3 muscarinic (M3) receptors in bronchial smooth muscle causing bronchodilation
Indications
Approved
- Asthma (Spiriva Respimat only)
- Chronic obstructive pulmonary disease
Off-label
- Asthma, severe symptomatic (children)
Contraindications
Source: Lexicomp
- Additional contraindications (not in US labeling): Hypersensitivity to atropine or its derivatives Absolute
- Hypersensitivity to ipratropium, tiotropium, or any component of the formulation Absolute
Adverse Reactions
Cardiac disorders (5)
Common angina pectoris · Chest pain · edema · hypertension · palpitations
Nervous system disorders (6)
Common depression · dizziness · Headache · insomnia · paresthesia · voice disorder
Renal and urinary disorders (1)
Common Urinary tract infection
Immune system disorders (1)
Common Hypersensitivity reaction
Metabolism and nutrition disorders (2)
Common Hypercholesterolemia · hyperglycemia
Gastrointestinal disorders (10)
Very Common Xerostomia
Common Abdominal pain · constipation · diarrhea · dyspepsia · gastroesophageal reflux disease · gastrointestinal disease · oropharyngeal candidiasis · stomatitis · vomiting
Skin and subcutaneous tissue disorders (2)
Common pruritus · Skin rash
Musculoskeletal and connective tissue disorders (5)
Common Arthralgia · arthritis · leg pain · myalgia · skeletal pain
Eye disorders (1)
Common Cataract
Infections and infestations (3)
Common Candidiasis · herpes zoster · infection
General disorders and administration site conditions (1)
Common Fever
Respiratory, thoracic and mediastinal disorders (10)
Very Common pharyngitis · sinusitis · Upper respiratory tract infection
Common allergic rhinitis · bronchitis · cough · epistaxis · flu-like symptoms · laryngitis · Rhinitis
Dosing
Source: Lexicomp
Warnings & Precautions
Source: Lexicomp
Bronchospasm
Paradoxical bronchospasm may occur with use of inhaled agents; discontinue use and consider other therapy if bronchospasm occurs.
CNS effects
May cause dizziness and blurred vision; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
Hypersensitivity reactions
Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm, anaphylaxis, itching) have been reported. Discontinue immediately if signs/symptoms occur. Use with caution in patients with a history of hypersensitivity to atropine. Disease-related concerns:
Glaucoma
May worsen symptoms of narrow-angle glaucoma; use with caution.
Prostatic hyperplasia/bladder neck obstruction
May worsen the symptoms of prostatic hyperplasia and/or bladder neck obstruction; use with caution.
Renal impairment
Use with caution in patients with moderate to severe renal impairment (CrCl ≤60 mL/minute); monitor closely for anticholinergic adverse events. Concurrent drug therapy issues:
Drug-drug interactions
Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:
Lactose
Capsule for oral inhalation may contain lactose; use with caution in patients with severe milk protein allergy. Other warnings/precautions:
Appropriate administration
Not indicated for the initial (rescue) treatment of acute episodes of bronchospasm.
Appropriate use
Spiriva HandiHaler: The contents of Spiriva capsules are for inhalation only via the HandiHaler device. Capsules should not be swallowed; there have been reports of incorrect administration (swallowing of the capsules).
Appropriate use
Spiriva Respimat: The contents of Spiriva inhalation spray are for inhalation only via the Respimat inhaler.
Avoid ocular contact
Avoid inadvertent instillation into the eyes; may dilate pupils and/or cause blurred vision.
Pregnancy & Lactation
Pregnancy
Adverse events have been observed in animal reproduction studies.
Lactation
It is not known if tiotropium is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Monitoring
| Clinical pearl | FEV1, peak flow (or other pulmonary function studies); anticholinergic adverse reactions (patients with CrCl ≤50 mL/min); signs and symptoms of narrow angle glaucoma and urinary retention |
|---|
Chemistry & Properties
| Formula | C19H22NO4S2+ |
|---|---|
| Molecular weight | 392.52 g/mol |
| IUPAC name | [(1S,2S,4R,5R)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate |
| CAS | 186691-13-4 |
| PubChem CID | 5487427 |
| InChIKey | LERNTVKEWCAPOY-DZZGSBJMSA-N |
| logP | 2.35 (XLogP 2.3) |
| Polar surface area | 59.06 Ų |
| H-bond acceptors / donors | 6 / 1 |
| Drug-likeness (QED) | 0.49 |
| Lipinski violations | 0 |
SMILES
C[N+]1(C)[C@@H]2C[C@@H](OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12Biology & Pharmacokinetics
Pharmacokinetics predicted
| Bioavailability | 70.0% |
|---|---|
| Half-life | 0.819 h |
| Volume of distribution | 38.829 L/kg |
| Protein binding | 72.1% |
| BBB penetrant | No |
Enzyme interactions
| Enzyme | Role | Detail |
|---|---|---|
| CYP1A2 | Inhibitor | — |
| CYP1A2 | Substrate | — |
| CYP2B6 | Inhibitor | — |
| CYP2C19 | Inhibitor | — |
| CYP2C19 | Substrate | — |
| CYP2C8 | Inhibitor | — |
| CYP2C9 | Inhibitor | — |
| CYP2C9 | Substrate | — |
| CYP2D6 | Substrate | — |
| CYP3A4 | Inhibitor | — |
| CYP3A4 | Substrate | — |
Transporters
BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OCT1 (Substrate)OCT2 (Substrate)OCTN2 (Substrate)P-gp (Substrate)
Drug–drug interactions (100+, DDInter)
| Interacting drug | Severity | Management |
|---|---|---|
| Acetylcholine | moderate | |
| Aclidinium | moderate | |
| Acrivastine | moderate | |
| Alimemazine | moderate | |
| Amitriptyline | moderate | |
| Amoxapine | moderate | |
| Aripiprazole | moderate | |
| Atropine | moderate | |
| Azatadine | moderate | |
| Belladonna | moderate | |
| Benzatropine | moderate | |
| Bethanechol | moderate | |
| Biperiden | moderate | |
| Brompheniramine | moderate | |
| Carbamoylcholine (ophthalmic) | moderate | |
| Carbinoxamine | moderate | |
| Cevimeline | moderate | |
| Chlorcyclizine | moderate | |
| Chlorpheniramine | moderate | |
| Chlorpromazine | moderate | |
| Clemastine | moderate | |
| Clidinium | moderate | |
| Clomipramine | moderate | |
| Clozapine | moderate | |
| Cyclizine | moderate | |
| Cyclobenzaprine | moderate | |
| Cyproheptadine | moderate | |
| Darifenacin | moderate | |
| Demecarium (ophthalmic) | moderate | |
| Desipramine | moderate | |
| Dexbrompheniramine | moderate | |
| Dicyclomine | moderate | |
| Dimenhydrinate | moderate | |
| Diphenhydramine | moderate | |
| Disopyramide | moderate | |
| Doxepin | moderate | |
| Doxepin (topical) | moderate | |
| Doxylamine | moderate | |
| Echothiophate (ophthalmic) | moderate | |
| Eluxadoline | moderate |
Showing 40 of 100+.
Registered Products (2)
| Brand | Form / strength | Pack | Agent | Citizen (JOD) |
|---|---|---|---|---|
| Spiriva Respimat | Cartridge (as Bromide)2.5 mcg/Puff | 4 ml | The Jordan Drugstore Co | 29.780 |
| Spiolto Respimat 2.5mcg +2.5mcg | Inhaler 2.5 mcg, 2.5 mcg | 1 Catridge + 1 Respimat | The Jordan Drugstore Co | 43.600 |