Tiotropium bromide and olodaterol

STIOLTO RESPIMAT is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA).

The drug substance tiotropium bromide monohydrate is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol.

The structural formula is:

Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br •H2O.

The drug substance olodaterol hydrochloride is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094.

The structural formula is:

The drug product, STIOLTO RESPIMAT, is composed of a sterile aqueous solution of tiotropium bromide and olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STIOLTO RESPIMAT cartridge) for use with the STIOLTO RESPIMAT inhaler.

Excipients include water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid.

The STIOLTO RESPIMAT cartridge is only intended for use with the STIOLTO RESPIMAT inhaler. The STIOLTO RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STIOLTO RESPIMAT inhaler has a light green-colored cap.

When used with the STIOLTO RESPIMAT inhaler each cartridge, containing 4 grams of sterile aqueous solution, delivers the labeled number of metered actuations after preparation for use. Each dose (one dose equals two actuations) from the STIOLTO RESPIMAT inhaler delivers 5 mcg tiotropium and 5 mcg olodaterol in 22.1 mcL from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).

LABA, such as olodaterol, one of the active components in STIOLTO RESPIMAT, increase the risk of asthma-related death. STIOLTO RESPIMAT is not indicated for the treatment of asthma [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
• Paradoxical bronchospasm [see WARNINGS AND PRECAUTIONS]
• Worsening of narrow-angle glaucoma [see WARNINGS AND PRECAUTIONS]
• Worsening of urinary retention [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.

The clinical program for STIOLTO RESPIMAT included 7151 subjects with COPD in two 52-week active-controlled trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled cross-over trials, and four additional trials of shorter duration. A total of 1988 subjects received at least 1 dose of STIOLTO RESPIMAT. Adverse reactions observed in the ≤ 12-week trials were consistent with those observed in the 52-week trials, which formed the primary safety database.

The primary safety database consisted of pooled data from the two 52-week double-blind, active-controlled, parallel group confirmatory clinical trials. These trials included 5162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1029 were treated with STIOLTO RESPIMAT once daily. The STIOLTO RESPIMAT group was composed of mostly Caucasians (71.1%) with a mean age of 63.8 years and a mean percent predicted FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and olodaterol 5 mcg were included as active control arms and no placebo was used.

In these two clinical trials, 74% of patients exposed to STIOLTO RESPIMAT reported an adverse reaction compared to 76.6% and 73.3% in the olodaterol 5 mcg and tiotropium 5 mcg groups, respectively. The proportion of patients who discontinued due to an adverse reaction was 7.4% for STIOLTO RESPIMAT treated patients compared to 9.9% and 9.0% for olodaterol 5 mcg and tiotropium 5 mcg treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD.

The most common serious adverse reactions were COPD exacerbation and pneumonia.

Table 1 shows all adverse drug reactions that occurred with an incidence of > 3% in the STIOLTO RESPIMAT treatment group and a higher incidence rate than the active comparator groups listed.

Table 1 : Number and frequency of adverse drug reactions greater than 3% (and higher than any of the comparators tiotropium and/or olodaterol) in COPD patients exposed to STIOLTO RESPIMAT: Pooled data from the two 52-week, double-blind, active-controlled clinical trials in COPD  patients 40 years of age and older

Other adverse drug reactions in patients receiving STIOLTO RESPIMAT that occurred in ≤ 3% of patients in clinical studies are listed below:

Metabolism and nutrition disorders: dehydration

Nervous system disorders: dizziness, insomnia

Eye disorders: glaucoma, intraocular pressure increased, vision blurred

Cardiac/vascular disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension

Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis

Gastrointestinal disorders: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including ileus paralytic

Skin and subcutaneous disorders: rash, pruritus, angioneurotic edema, urticaria, skin infection, and skin ulcer, dry skin, hypersensitivity (including immediate reactions)

Musculoskeletal and connective tissue disorders: arthralgia, joint swelling

Renal and urinary disorders: urinary retention, dysuria, and urinary tract infection

Included as part of the PRECAUTIONS section.

Tiotropium bromide/olodaterol is a prescription medication used to treat airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

It is a single product containing two medications: tiotropium and olodaterol. Tiotropium belongs to a group of drugs called bronchodilators. It works by relaxing and opening the air passages to the lungs to make breathing easier. Olodaterol belongs to a group of drugs called long-acting beta-agonists (LABAs). It works by relaxing and opening air passages in the lungs, making it easier to breathe. Tiotropium bromide/olodaterol helps the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath.

This medication comes as an inhalation spray and is taken usually once a day.

Common side effects of this medication include runny nose, cough, and back pain. 

Tiotropium bromide/olodaterol is a prescription medication used to treat airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tiotropium bromide and olodaterol may be found in some form under the following brand names:

• Stiolto Respimat

Serious side effects have been reported with tiotropium bromide/olodaterol. See the "Drug Precautions" sections.

Common side effects include:

• runny nose
• cough
• back pain
• dizziness
• difficulty falling or staying asleep
• blurred vision
• glaucoma
• dry mouth
• constipation
• rash
• dry skin
• urinary retention

This is not a complete list of tiotropium bromide/olodaterol side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Before using tiotropium bromide/olodaterol tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to tiotropium bromide/olodaterol or any of its ingredients, any other medicines, or food products.
• have heart problems
• have high blood pressure
• have seizures
• have thyroid problems
• have diabetes
• have eye problems, such as glaucoma. This medication can make your glaucoma worse.
• have prostate or bladder problems, or problems passing urine. This medication can make these problems worse.
• have any other medical conditions
• are pregnant or planning to become pregnant. It is not known if this medication can harm your unborn baby.
• are breastfeeding. It is not known if tiotropium bromide/olodaterol passes into your breast milk and if it can harm your baby.

Tell your doctor about all the medications you take including prescription and non-prescription medicines, vitamins, and herbal supplements.