Spiriva HandiHaler

Respiratory Long-Acting Muscarinic Antagonists (LAMA)

For inhalation use only.
Administer at the same time each day.
 
Inhalation Powder (Spiriva HandiHaler):
Instruct patients NOT to swallow the capsules; cases of inadvertent oral administration have been reported to the FDA.
The dry-powder capsule inhaler (HandiHaler) delivers drug at inspiratory rates as low as 20 L/minute. Patients with severe COPD (FEV1 <= 27% of predicted) have demonstrated successful use of the HandiHaler.
Open and prepare mouthpiece of HandiHaler according to package instructions.
Load the oral inhaler with an inhalation capsule immediately prior to use (see package insert). Discard any capsule that is exposed to air (opened and not used immediately). Place a single capsule in the device. Press the button to puncture the capsule.
To inhale a dose: Hold the mouthpiece level to, but away from, the mouth, and exhale fully. Then, put the mouthpiece to the mouth, tightly close lips, and breathe in the dose deeply and slowly; inhale so as to hear or feel the capsule vibrate within the inhaler. Remove the HandiHaler from the mouth, hold breath for at least 10 seconds, and then exhale slowly away from the inhaler. To ensure full dose delivery, repeat deep exhale and slow inhale from HandiHaler a second time. Do not press the button to puncture the capsule a second time.
If the capsule does not vibrate during inhalation of the medicine, gently tap the inhaler on a table while holding it in an upright position. Verify that the mouthpiece is closed properly and repeat administration. Do not press the button to pierce the capsule again. Advise patients to contact their health care professional to review correct administration technique if the capsule still does not vibrate while inhaling.
Occasionally the gelatin capsule might break into very small pieces which pass through the inhaler screen and reach the mouth or throat. Advise patients that this is normal and not expected to cause harm.
After administration, instruct patient to dispose of the used capsule prior to storing the inhaler and to rinse mouth with water to minimize dry mouth.
To avoid the spread of infection, do not use the HandiHaler device for more than one person.
The HandiHaler may be rinsed with warm water and air dried as needed, according to package instructions. Do not use the inhaler device when it is wet.
 
Inhalation spray (Spiriva Respimat):
Instruct patient on proper inhalation technique according to product directions.
Prior to first use, insert the cartridge into the inhaler and prime the unit by actuating the inhaler toward the ground until an aerosol cloud is visible and then repeating the process 3 more times. The unit is then considered primed and ready for use. Do not remove the cartridge once it has been inserted into the inhaler. If the inhaler is not used for more than 3 days, actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, actuate the inhaler until an aerosol cloud is visible and then repeat the process 3 more times to prepare the inhaler for use.
To inhale a dose: Hold the inhaler upright with the cap closed, so as to not accidentally release a dose of medicine. Turn the clear base in the direction of the arrows on the label until it clicks (half a turn). Then, flip the cap until it snaps fully open. Have patient breathe out slowly and fully, and then close their lips around the end of the mouthpiece without covering the air vents. Point the inhaler to the back of the throat. While the patient takes in a slow, deep breath through the mouth, press the dose release button and continue to have the patient breathe in slowly for as long as the patient can. The patient should hold the breath for 10 seconds or for as long as comfortable. These steps should be repeated twice to receive the proper dose of medicine. After the second inhalation, close the cap until it is time to use the inhaler again.
The mouthpiece, including the metal part inside the mouthpiece, should be cleaned with a damp cloth or tissue only, at least 1 time a week; any minor discoloration in the mouthpiece does not affect the inhaler. If the outside of the inhaler gets dirty, wipe it with a damp cloth.
The inhaler contains either 60 puffs (equal to 30 doses of medicine) or 28 puffs (equal to 14 doses of medicine) after prepared for the first use. The dose indicator shows approximately how much medicine is left. When the pointer enters the red area of the scale, there is enough medicine for 7 days (30 dose product) or 3 days (14 dose product); once the dose indicator has reached the end of the scale, all puffs have been used and the inhaler locks automatically. At this point, the base cannot be turned any further.
The inhaler should be discarded 3 months after insertion of cartridge into inhaler, even if all the medicine has not been used, or when the inhaler is locked, whichever comes first.

angioedema / Rapid / 0-2.0
GI obstruction / Delayed / 0-1.0
ileus / Delayed / 0-1.0
atrial fibrillation / Early / Incidence not known
ocular hypertension / Delayed / Incidence not known
visual impairment / Early / Incidence not known
prostatic hypertrophy / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
laryngospasm / Rapid / Incidence not known
laryngeal edema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known

constipation / Delayed / 1.0-5.1
peripheral edema / Delayed / 3.0-5.0
depression / Delayed / 1.0-4.4
candidiasis / Delayed / 1.0-4.0
stomatitis / Delayed / 1.0-3.0
palpitations / Early / 0.5-3.0
dysphonia / Delayed / 0.5-3.0
cataracts / Delayed / 1.0-3.0
hypercholesterolemia / Delayed / 1.0-3.0
hyperglycemia / Delayed / 1.0-3.0
hypertension / Early / 1.0-2.0
elevated hepatic enzymes / Delayed / 1.0-2.0
dysphagia / Delayed / 0-1.0
dysuria / Early / 0-1.0
urinary retention / Early / 0-1.0
skin ulcer / Delayed / 0-1.0
dehydration / Delayed / 0-1.0
chest pain (unspecified) / Early / 0.5-0.9
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
corneal edema / Early / Incidence not known
blurred vision / Early / Incidence not known
urethral pain / Early / Incidence not known

infection / Delayed / 0-43.0
xerostomia / Early / 4.1-16.0
pharyngitis / Delayed / 7.0-15.9
sinusitis / Delayed / 2.7-11.0
dyspepsia / Early / 1.0-6.0
abdominal pain / Early / 0.5-6.0
rhinitis / Early / 0.5-6.0
cough / Delayed / 1.0-5.8
headache / Early / 3.8-5.7
insomnia / Early / 0.5-4.4
arthralgia / Delayed / 0.5-4.2
vomiting / Early / 1.0-4.0
epistaxis / Delayed / 0-4.0
myalgia / Early / 4.0-4.0
rash / Early / 1.0-4.0
gastroesophageal reflux / Delayed / 0.5-3.0
dizziness / Early / 1.0-3.0
paresthesias / Delayed / 1.0-3.0
pruritus / Rapid / 1.0-3.0
laryngitis / Delayed / 0-3.0
musculoskeletal pain / Early / 1.0-3.0
diarrhea / Early / 1.0-2.0
fever / Early / 1.0-2.0
gingivitis / Delayed / 0-1.0
xerosis / Delayed / 0-1.0
hoarseness / Early / Incidence not known
throat irritation / Early / Incidence not known
ocular irritation / Rapid / Incidence not known
ocular pain / Early / Incidence not known
urticaria / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known

Spiriva HandiHaler, Spiriva Respimat

Rx

Inhaled long-acting muscarinic antagonist (LAMA); administered once daily; minimal side effects except for xerostomia
Used for maintenance treatment of COPD in adults
Also approved for maintenance treatment of asthma in adult and pediatric patients 6 years and older

2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily. It may take up to 4 to 8 weeks of therapy to see the maximum benefit in lung function in asthmatic patients.[58075]

2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily. It may take up to 4 to 8 weeks of therapy to see the maximum benefit in lung function in asthmatic patients.[58075]

Efficacy has not been established; safety has been studied. 2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily was delivered with the AeroChamber Plus Flow-Vu valved holding chamber with facemask. The adverse reaction profile in the treated group (mean age: 3.1 years) was similar to that observed in adult and older pediatric patients.

2 actuations (2.5 mcg/actuation) via oral inhalation once daily (total daily dose: 5 mcg) at the same time each day, is the usual and max dosage. Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently.[58075] According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, tiotropium may be used as initial monotherapy in all groups of COPD patients; however, combination therapy with a long-acting beta-agonist (LABA) or inhaled corticosteroid (ICS) may be needed in patients in Group D or those patients still experiencing dyspnea or exacerbations upon follow-up.[63765] In clinical trials, tiotropium improved COPD symptoms, improved general health status, and reduced exacerbation rates and hospitalizations. Dyspnea, as a secondary endpoint, has been shown to be improved.[63765] [27138] [27142] [27144] [37001] [63764]

2 oral inhalations of the contents of a single capsule (18 mcg) once daily using the Handihaler device at the same time each day. Max: 18 mcg/24 hours (contents of 1 inhalation capsule). Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, tiotropium may be used as initial monotherapy in all groups of COPD patients; however, combination therapy with a long-acting beta-agonist (LABA) or inhaled corticosteroid (ICS) may be needed in patients in Group D or in patients still experiencing dyspnea or exacerbations upon follow-up. In clinical trials, tiotropium improved COPD symptoms, improved general health status, and reduced COPD exacerbation rates and hospitalizations. Dyspnea, as a secondary endpoint, has been shown to be improved.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Monitor patients with moderate to severe renal impairment (CrCl < 60 mL/minute) for anticholinergic effects.

Aclidinium: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Aclidinium; Formoterol: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Anticholinergics: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Atropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Atropine; Difenoxin: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Belladonna; Opium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Benztropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Chlordiazepoxide; Clidinium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Dicyclomine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Diphenoxylate; Atropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Flavoxate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Glycopyrrolate; Formoterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Homatropine; Hydrocodone: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Hyoscyamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Indacaterol; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Methacholine: (Major) Discontinue use of tiotropium 168 hours or more before a methacholine challenge test. Tiotropium inhibits the airway response to methacholine.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Methscopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Neostigmine; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Oxybutynin: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Propantheline: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Trihexyphenidyl: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.

Spiriva HandiHaler/Tiotropium Respiratory (Inhalation) Pwd: 18mcg
Spiriva Respimat Respiratory (Inhalation) Spray Met: 1actuation, 1.25mcg, 2.5mcg

2.5 mcg/day for asthma or 5 mcg/day for COPD for inhalation spray; 18 mcg/day for dry powder inhaler.

2.5 mcg/day for asthma or 5 mcg/day for COPD for inhalation spray; 18 mcg/day for dry powder inhaler.

2.5 mcg/day for inhalation spray.

6 to 12 years: 2.5 mcg/day for inhalation spray.
6 years and younger: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Tiotropium antagonizes the action of acetylcholine by blocking muscarinic cholinergic receptors. The parasympathetic nervous system has an important role in the automatic control of the airways and is responsible for resting bronchomotor tone. Tiotropium has both bronchodilatory and bronchoprotective actions and is antagonistic at M1, M2, and M3 muscarinic receptors. Each muscarinic receptor serves a unique physiological function. M1 receptors facilitate cholinergic neurotransmission via parasympathetic ganglia. M2 receptors, located on post-ganglionic cholinergic nerves, modulate negative feedback for acetylcholine release. M3 receptors, found on bronchial smooth muscle and mucous glands, are responsible for the airway contraction and mucous secretion in response to acetylcholine. Tiotropium is selective for and dissociates slowly from M1 and M3 receptors (which mediate bronchoconstriction), and dissociates more rapidly from M2 receptors (which inhibit acetylcholine release from cholinergic nerve endings). In the lung, this receptor antagonism and slow dissociation results in bronchodilation and a 24-hour duration of action. The half-lives for release of tiotropium from the M1, M2 and M3 receptors are 14.6, 3.6 and 34.7-hours, respectively. Tiotropium is 10-fold more potent than ipratropium. For all receptor subtypes, tiotropium dissociates more slowly than ipratropium (0.04 to 0.26-hour half-life). Dose-ranging studies have shown that increases in FEV1 are dose-dependent up to a 72 mcg single dose with values remaining above baseline FEV1 for 72 hours.

Tiotropium is administered as a dry-powder via oral inhalation and as an inhalation spray. A pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the inhalation spray (5 mcg inhaled dose) and as inhalation powder (18 mcg inhaled dose) resulted in a similar systemic exposure between the two products. After intravenous dosing, tiotropium is 72% protein bound with a Vd of 32 L/kg; local concentrations in the lung are not known, but expected to be higher with orally inhaled administration. Animal studies have shown tiotropium does not penetrate the blood-brain barrier. In an unpublished study, accumulation of tiotropium did not occur in the plasma or urine once steady-state was achieved. Approximately 7% of the delivered dose (roughly equivalent to 0.25 mcg) appears unchanged in the urine at steady-state. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (25% of an intravenous dose) is metabolized by CYP450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. It appears the drug and its metabolites are mostly excreted renally. In a pharmacokinetic study, 74% of intravenously administered tiotropium was excreted in urine as unchanged drug. After once daily administration of the inhalation spray, the terminal half-life of tiotropium in COPD and asthma patients is 25 and 44 hours, respectively. Terminal elimination half-life is between 5 to 6 days after dry-powder inhalation.
 
Affected Cytochrome P450 (CYP 450) enzymes and drug transporters: CYP2D6, CYP3A4
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (25% of an intravenous dose) is metabolized by CYP450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited by CYP2D6 and 3A4 inhibitors. Thus, CYP2D6 and CYP3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

After oral inhalation, there is minimal systemic absorption of tiotropium, reducing the chance for systemic side effects. Roughly 20% of a dose is deposited in the lung. The onset of action is within 30 minutes, but duration of action is close to 24 hours allowing once-daily dosing. Peak effects (increase in FEV1 of 19% to 26% greater than baseline) occur in roughly 1 to 4 hours. Peak and trough plasma concentrations are roughly 16 ng/L and 4 ng/L, respectively, although plasma concentrations are not used to monitor clinical response. Peak concentrations are achieved in 5 to 7 minutes, and trough concentrations in less than 60 minutes. Increases in FEV1 are dose-related; trough FEV1 and FVC average greater than 12% over baseline one week after tiotropium administration. After long-term once-daily inhalation, steady state is achieved within 1 week in COPD and asthma patients receiving the inhalation spray and 2 to 3 weeks in COPD patients receiving the dry-powder inhaler. For asthma, maximum bronchodilator effect may take up to 4 to 8 weeks.

There are no adequate and well controlled studies of tiotropium in pregnant women. The limited data with tiotropium during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. No structural abnormalities were observed during animal reproduction studies in pregnant rats and rabbits, however, increased post-implantation loss was observed when tiotropium was administered at maternally toxic doses. Tiotropium should only be used during pregnancy if the potential benefit to the mother outweighs any potential risks to the fetus. The safety and effectiveness of tiotropium has not been studied during labor and delivery.

There is no data on the presence of tiotropium in human milk, the effects on the breast-feeding infant, or the effects on milk production. Tiotropium is present in lactating rats; however, it is not known whether tiotropium is excreted in human breast-milk. However, because of low systemic concentrations in the mother and poor absorption from the gastrointestinal tract (i.e. 2% to 3%), it is unlikely that maternal use of tiotropium would result in clinically significant exposure to a breast-feeding infant. As with all medications, if the drug is used in a breast-feeding mother, the infant should be monitored for possible adverse effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.