Myozyme 50 mg, powder for concentrate for solution for infusion

1. Name Of The Medicinal Product

Myozyme 50 mg powder for concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One vial contains 50 mg of alglucosidase alfa.

After reconstitution, the solution contains 5 mg of alglucosidase* alfa per ml and after dilution, the concentration varies from 0.5 mg to 4 mg/ml.

*Human acid α-glucosidase is produced in Chinese hamster ovary cells (CHO) by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for concentrate for solution for infusion.

White to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Myozyme is indicated for long-term enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of Pompe disease (acid α-glucosidase deficiency).

Myozyme is indicated in adults and paediatric patients of all ages.

In patients with late-onset Pompe disease the evidence of efficacy is limited (see section 5.1).

4.2 Posology And Method Of Administration

Myozyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.

Posology

The recommended dose regimen of alglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks.

Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease.

Paediatric and elderly population

There is no evidence for special considerations when Myozyme is administered to paediatric patients of all ages or elderly patients.

Renal and hepatic impairment

The safety and efficacy of Myozyme in patients with renal or hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.

Method of administration

Myozyme should be administered as an intravenous infusion.

Infusions should be administered incrementally. It is recommended that the infusion begin at an initial rate of 1 mg/kg/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs of infusion associated reactions (IARs) until a maximum rate of 7 mg/kg/h is reached. IARs are described in section 4.8.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Life threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients, when rechallenge was unsuccessful (see sections 4.4 and 4.8).

4.4 Special Warnings And Precautions For Use

Hypersensitivity/Anaphylactic reactions

Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reported in infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of the potential for severe infusion associated reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered. If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of Myozyme infusion should be considered and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed.

Infusion Associated Reactions

Approximately half of the patients treated with Myozyme in infantile-onset clinical studies and 28% of the patients treated with Myozyme in a late-onset clinical study developed infusion associated reactions (IARs). IARs are defined as any related adverse event occurring during the infusion or during the hours following infusion. Some reactions were severe (see section 4.8). A tendency was observed in infantile patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs. Infantile onset patients who develop high antibody titres appear to be at higher risk for developing more frequent IARs. Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration of Myozyme. Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported to the marketing authorisation holder.

Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with caution when re-administering Myozyme (see sections 4.3 and 4.8). Mild and transient effects may not require medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics and/or corticosteroids, has effectively managed most reactions. IARs may occur at any time during the infusion of Myozyme or generally up to 2 hours after, and are more likely with higher infusion rates.

Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion associated reactions. Therefore, these patients should be monitored more closely during administration of Myozyme.

Immunogenicity

In clinical studies, the majority of patients developed IgG antibodies to rhGAA typically within 3 months of treatment. Thus seroconversion is expected to occur in most patients treated with Myozyme. A tendency was observed for infantile-onset patients treated with a higher dose (40 mg/kg) to develop higher titers of antibodies. There does not appear to be a correlation between the onset of IARs and the time of IgG antibody formation. A limited number of the IgG positive patients evaluated tested positive for inhibitory effects on in vitro testing. Due to the rarity of the condition and the limited experience to date, the effect of antibody formation on safety and efficacy is currently not fully established. The probability of a poor outcome and of developing high and sustained antibody titers appears higher among CRIM-negative patients (Cross Reactive Immunologic Material; patients in whom no endogenous GAA protein was detected by Western blot analysis) than among CRIM-positive patients (patients in whom endogenous GAA protein was detected by Western blot analysis). However, high and sustained antibody titers also occur in some CRIM-positive patients. The cause of a poor clinical outcome and of developing high and sustained antibody titers is thought to be multi-factorial. IgG antibody titers should be regularly monitored.

Patients who experience hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies to Myozyme appear to be at a higher risk for the occurrence of IARs when Myozyme is re-administered (see section 4.8). Therefore, these patients should be monitored more closely during administration of Myozyme. Some IgE positive patients were successfully rechallenged with Myozyme using a slower infusion rate at lower initial doses and have continued to receive Myozyme under close clinical supervision.

Transient nephrotic syndrome

Transient nephrotic syndrome which resolved following temporary interruption of ERT was observed in one patient with infantile-onset Pompe disease who received very frequent dosing of rhGAA (10 mg/kg 5 times weekly) over an extended period.

Immune complex-mediated reactions

Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa, including ulcerative and necrotizing skin lesions (see section 4.8). Patients should be monitored for signs and symptoms of systemic immune complex-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, discontinuation of the administration of alglucosidase alfa should be considered and appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been successfully rechallenged and continued to receive alglucosidase alfa under close clinical supervision.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions studies have been performed. Because it is a recombinant human protein, alglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

4.6 Pregnancy And Lactation

Pregnancy

There are no data from the use of alglucosidase alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Myozyme should not be used during pregnancy unless clearly necessary.

Breast-feeding

Alglucosidase alfa may be excreted in breast milk. Because there are no data available on effects in neonates exposed to alglucosidase alfa via breast milk, it is recommended to stop breast-feeding when Myozyme is used.

Fertility

There are no clinical data on the effects of alglucosidase alfa on fertility. Preclinical data did not reveal any significant adverse findings (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Because dizziness has been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.

4.8 Undesirable Effects

Infantile-onset Pompe disease

In clinical trials, 39 infantile-onset patients were treated with Myozyme for more than three years (168 weeks with a median of 121 weeks; see section 5.1). Adverse reactions reported in at least 2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild to moderate in intensity and almost all occurred during the infusion or during the 2 hours following the infusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnea, periorbital edema and hypertension have been reported.

Late-onset Pompe disease

In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to 70 years, were treated with Myozyme or placebo randomized in a 2:1 ratio (see section 5.1). Overall, the numbers of patients experiencing adverse reactions and serious adverse reactions were comparable between the two groups. The most common adverse reactions observed were IARs. Slightly more patients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). The majority of these reactions were non-serious, mild to moderate in intensity and resolved spontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adverse reactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throat tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients were IgE-mediated hypersensitivity reactions.

Table 1: Adverse reactions (reported in at least 2 patients) and adverse reactions reported in post-marketing setting, expanded access programs and non-controlled clinical trials, per System Organ Class, presented by frequency categories: very common (

System Organ Class	Frequency	Adverse reaction (Preferred Term Level)	Additional adverse reactions4 Infantile- and Late-onset Pompe disease
Infantile-onset Pompe disease1	Late-onset Pompe disease2
Immune system disorders	common		Hypersensitivity
Psychiatric disorders	common	Agitation
not known			Agitation Restlessness
Nervous system disorders	common	Tremor	Dizziness Paraesthesia Headache3
not known			Tremor Headache
Eye disorders	not known			Conjunctivitis
Cardiac disorders	very common	Tachycardia
common	Cyanosis
not known			Cardiac arrest Bradycardia Tachycardia Cyanosis
Vascular disorders	very common	Flushing
common	Hypertension Pallor	Flushing
not known			Hypertension Hypotension Pallor
Respiratory, thoracic and mediastinal disorders	very common	Tachypnoea Cough
common		Throat tightness
not known			Respiratory arrest Apnea Respiratory distress Bronchospasm Wheezing Pharyngeal oedema Dyspnoea Tachypnoea Throat tightness Cough
Gastrointestinal disorders	very common	Vomiting
common	Retching Nausea	Diarrhoea Vomiting Nausea3
not known			Abdominal pain Retching
Skin and subcutaneous tissue disorders	very common	Urticaria Rash
common	Erythema Rash maculopapular Rash macular Rash papular Pruritus	Urticaria Rash papular Pruritus Hyperhidrosis
not known			Periorbital edema Livedo reticularis Lacrimation increased Rash Erythema Hyperhidrosis
Musculoskeletal and connective tissue disorders	common		Muscle spasms Muscle twitching Myalgia
not known			Arthralgia
General disorders and administration site conditions	very common	Pyrexia
common	Irritability Chills	Pyrexia Chest discomfort Peripheral oedema Local swelling Fatigue3 Feeling hot
not known			Chest pain Face edema Feeling hot Pyrexia Chills Chest discomfort Irritability Peripheral coldness Infusion site pain Infusion site reaction
Investigations	very common	Oxygen saturation decreased
common	Heart rate increased Blood pressure increased Body temperature increased	Blood pressure increased
not known			Oxygen saturation decreased Heart rate increased

¹ Reactions reported in 39 infantile-onset patients in 2 clinical trials

² Reactions reported in 60 late-onset patients in a placebo-controlled clinical trial

³ Reactions reported more frequently in the placebo group than in the Myozyme group in late-onset patients

⁴ Additional adverse reactions from post-marketing, expanded access programs and non-controlled clinical trials.

A small number of patients (<1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures. Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, edematous and/or cutaneous in nature (see section 4.4).

Patients with moderate to severe or recurrent IARs have been evaluated for Myozyme specific IgE antibodies; some patients tested positive including some who experienced an anaphylactic reaction.

Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4).

4.9 Overdose

There is no experience with overdose of alglucosidase alfa. In clinical studies doses up to 40 mg/kg body weight were used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes.

ATC code: A16AB07.

Pompe disease

Pompe disease is a rare, progressive and fatal metabolic myopathy with an estimated global incidence of 1 in 40,000 births. Other names for Pompe disease include glycogen storage disease type II (GSD-II), acid maltase deficiency (AMD) and glycogenosis type II. Pompe disease belongs to the lysosomal storage disorders as it is caused by a deficiency of a naturally-occurring lysosomal hydrolase, acid α-glucosidase (GAA) that degrades lysosomal glycogen to glucose. Deficiency of this enzyme leads to glycogen accumulation in various tissues, particularly cardiac, respiratory and skeletal muscle, leading to the development of hypertrophic cardiomyopathy and progressive muscle weakness, including impairment of respiratory function.

The clinical presentation of Pompe disease can be described as a spectrum of disease which ranges from a rapidly-progressing infantile-onset form (onset of symptoms of Pompe disease typically within the first year of life and a very short expected life-span) to a less rapidly-progressing late-onset form.

The infantile-onset form of Pompe disease is characterised by massive deposition of glycogen in the heart, and skeletal muscle always resulting in rapidly progressive cardiomyopathy, generalised muscle weakness and hypotonia. Motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death typically occurs due to cardiac and/or respiratory failure before the age of one year.

In a retrospective natural history study in patients with infantile-onset Pompe disease (n=168), the median age at onset of symptoms was 2.0 months and the median age of death was 9.0 months. Kaplan-Meier survival rates at 12, 24 and 36 months of age were 26%, 9% and 7%, respectively.

A non-typical, more slowly progressive form of infantile-onset Pompe disease has been described which is characterised by a less severe cardiomyopathy and consequently a more prolonged survival.

The late-onset form of Pompe disease manifests during infancy, childhood, adolescence or even adulthood and is much less rapidly progressive than the infantile-onset form. Usually, it is characterised by the presence of sufficient residual GAA activity to preclude the development of cardiomyopathy, however some cardiac involvement has been reported in up to approximately 4% of patients with late-onset Pompe disease.

Patients with late-onset Pompe disease typically present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and varying degrees of respiratory involvement, ultimately progressing to profound disability and/or the need for ventilatory support. The time course of disease progression is extremely variable and not predictable, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others presenting with a dissociation in the progression of skeletal and respiratory muscle involvement.

It is postulated that Myozyme will restore lysosomal GAA activity resulting in stabilisation or restoration of cardiac and skeletal muscle function (including respiratory muscles). Due to the blood-brain barrier effect and the enzyme's size, uptake of alglucosidase alfa in the central nervous system is unlikely.

Infantile-onset Pompe disease; clinical trial in patients aged 6 months or less

The safety and efficacy of Myozyme was assessed in a pivotal, randomised, open-label, historically-controlled clinical trial of 18 non-ventilated infantile-onset patients aged 6 months or less at the onset of treatment. The untreated historical cohort was matched to the pivotal study population and was derived from a retrospective natural history study (n=42) in patients with infantile-onset Pompe disease. Patients were randomized to receive either 20 mg/kg or 40 mg/kg once every two weeks for a period of 52 weeks. After a minimum of 52 weeks, 16 of these 18 patients were enrolled in an extension study to receive continued treatment at the same dose for a total duration of up to three years (150 weeks).

The primary endpoint was the proportion of patients who were alive and free of invasive ventilator support. However, the invasive ventilator-free survival was not recorded in the untreated historical cohort and a comparison of this endpoint is not possible. After 52 weeks of treatment, all 18 patients treated with Myozyme were alive and 15 of these 18 patients were alive and free of invasive ventilatory support whereas 1 of 42 patients in the untreated historical cohort was alive at 18 months of age. Two patients died and did not enter into the extension study. After 104 weeks of treatment, all 16 patients who enrolled in the extension study were alive and 10 of these 16 patients were free of invasive ventilatory support. At the end of the study (with individual patient treatment durations ranging from 60 to 150 weeks; mean follow-up period of 119 weeks) 14 of 16 patients were alive and 9 of 16 patients were alive and free of invasive ventilatory support. One additional patient died after study end and another one after withdrawal from the study.

Comparison of survival curves from time of diagnosis versus the untreated historical cohort was made using a Cox proportional hazards regression analysis. Patients treated with Myozyme demonstrated prolonged survival as compared to survival in an untreated historical cohort (see Table 2).

Table 2: Results for endpoint survival using the Cox regression model

Treated Patients	Historical Reference Comparator	Endpoint	Treatment Effect Hazard Ratio	95% Confidence Interval	p-value
N=18	N=42	Survival	0.05	(0.015, 0.147)	<0.0001
Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects were aged 6 months or less at the onset of treatment. Subjects in the untreated historical cohort were born in 1993 or later.

Echocardiographic indices of cardiomyopathy improved as measured by a decrease in left ventricular mass (LVM). After 52 weeks of treatment, LVM decreased from baseline in all 14 patients with available data and was within normal limits in 3 of 14 patients. After the first year (64 up to 130 weeks) of treatment LVM further decreased in 8 patients. At 104 weeks of treatment LVM assessments were available for 8 patients, of which 5 decreased to within normal limits.

As measured by motor performance age-equivalent scores of the Alberta Infant Motor Scale (AIMS), seven of the 18 patients made motor development gains during the study and were walking independently by the last study assessment (with individual patient treatment durations ranging from 52 to 130 weeks; mean follow-up period of 94 weeks). An additional 4 patients made motor development gains during the study and were sitting independently by the last study assessment (with individual patient treatment durations ranging from 78 to 130 weeks; mean follow-up period of 110 weeks), although they did not have functional use of the legs. The remaining 7 patients made no clinically significant motor gains or were unable to sustain the motor gains made and had very limited motor movement by the last study assessment (with individual patient treatment durations ranging from 52 to 142 weeks; mean follow-up period of 103 weeks).

After 52 weeks of treatment 14 of 18 patients (77.8%) had maintained or improved weight-for-age percentiles (above the 3rd percentile), 14 of 15 patients (93.3%) were above the 3rd percentile for length and 12 of 15 patients (80.0%) were above the 3rd percentile for head circumference. In the second year of treatment, 15 out of 17 patients had further improved weight-for-age percentiles (with individual patient treatment durations ranging from 78 to 142 weeks; mean follow-up period of 111 weeks), 10 out of 16 patients had further improved length-for-age percentiles (with individual patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 113 weeks) and 11 out of 15 patients had further improved head circumference-for-age percentiles (with individual patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 110 weeks). At 104 weeks of treatment, all 13 patients with available data had maintained or improved weight-for-age percentiles (above the 3rd percentile), all 12 patients with available data were above the 3rd percentile for length and all 12 patients with available data were above the 3rd percentile for head circumference.

Analyses of efficacy did not reveal meaningful differences between the 2 dose groups with respect to survival, invasive ventilator-free survival, any ventilator-free survival, decrease in LVM, gains in growth parameters and acquisition of motor milestones. Based on these results the 20 mg/kg qow dose is recommended.

Infantile-onset Pompe disease; clinical trial in patients aged 6 months to 3.5 years

A second open-label clinical trial also assessed the safety and efficacy of Myozyme in 21 patients with predominantly a non-typical form of infantile-onset Pompe disease who ranged in age from 6 months to 3.5 years at initiation of treatment. Patients received 20 mg/kg Myozyme once every two weeks for 52 weeks except for 8 patients who received 40 mg/kg after at least 26 weeks of treatment. After 52 weeks all patients continued treatment for a total duration of more than 3 years (168 weeks with a median of 121 weeks).

The primary endpoint of the pivotal trial was the proportion of patients who were alive. After 52 weeks of treatment, 16 of 21 patients (76.2%) treated with Myozyme were alive. After 104 weeks of treatment, 14 of 21 patients (66.7%) were alive and 1 patient was alive but had discontinued from the study. These proportions were maintained up to the end of the study (with individual patient treatment durations ranging from 1 to 168 weeks; mean follow-up period of 109 weeks). In the untreated historical cohort 5 of 47 patients (10.6%) for whom data were available, were alive at age 30 months (2.5 years).

Survival in the treated patients was compared to survival in a similar historical cohort of untreated subjects using a Cox proportional hazards regression analysis (See Table 3).

Table 3: Results for endpoint survival using the Cox regression model

Treated Patients	Historical Reference Comparator	Endpoint	Treatment Effect Hazard Ratio	95% Confidence Interval	p-value
N=21	N=48	Survival	0.301	(0.112,0.804)	0.0166
Note: Results are from a Cox proportional hazards regression analysis which includes treatment as a time-varying covariate, and also includes age of diagnosis and age at symptom onset. Subjects ranged in age from 6 months to 3.5 years at initiation of treatment. Subjects in the untreated historical cohort were born in 1995 or later.

Additional efficacy data showed that of 16 patients who were free of invasive-ventilator support at baseline, 7 remained so after 104 weeks of treatment. The 9 remaining patients either died (5 patients) or became invasive-ventilator dependent (4 patients). All 5 patients who were receiving invasive ventilation at baseline continued to require ventilation throughout the study (4 patients survived beyond week 104 and one patient died).

After 52 weeks of treatment, LVM decreased from baseline in all 12 patients with available data and was within normal limits in 6 of 12 patients. After the first year (58 up to 168 weeks) of treatment LVM further decreased in 9 out of 12 patients with available data. At 104 weeks of treatment LVM assessments were available for 10 patients, of which 9 decreased to within normal limits.

After 52 weeks of treatment, 3 out of 8 patients with available data made gains in motor function over baseline as measured by raw scores and age-equivalent scores from baseline in the AIMS. Six of the 11 patients with available data continued to make motor development gains beyond Week 52 (with individual patient treatment durations ranging from 58 to 168 weeks; mean follow-up period of 121 weeks), including 3 patients ambulatory and 3 patients with only functional sitting skills by the last study visit. The remaining 5 patients showed no significant change in motor development beyond Week 52 (with individual patient treatment durations ranging from 104 to 168 weeks; mean follow-up period of 140 weeks), including 4 patients with no significant motor skills in any of the positions evaluated and 1 patient with only functional sitting skills by the last study visit.

The vast majority of patients with infantile-onset Pompe disease treated with Myozyme demonstrate improvement in cardiac function as well as stabilisation or improvements in growth parameters. However, motor and respiratory responses to treatment have been more variable.

Patients with infantile-onset Pompe disease who demonstrated motor gains, had greater preservation of motor function and lower glycogen content in the quadriceps muscle at baseline. It is noteworthy that a higher proportion of patients with better motor outcomes show stability or improvement in growth parameters (weight), while the large majority of patients, regardless of their motor outcomes or baseline features, show reversal of cardiomyopathy as measured by changes in LVM Z-score.

The totality of the data suggests that early diagnosis and treatment at an early stage of disease may be critical to achieve the best outcomes in these infantile onset patients.

Late-onset Pompe disease

The safety and efficacy of Myozyme was assessed in a randomized, double-blind, placebo-controlled study in 90 patients with late-onset Pompe disease who ranged in age from 10 to 70 years at initiation of treatment and were all naive to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received 20 mg/kg Myozyme (n=60) or placebo (n=30) once every two weeks for 78 weeks (18 months).

The co-primary efficacy outcome assessments were distance walked (meters) in 6 minutes (6-Minute Walk Test, 6MWT) and FVC (Forced Vital Capacity) % predicted in the sitting position. After 78 weeks, patients treated with Myozyme showed improvement in distance walked as measured by 6MWT and stabilization of pulmonary function as measured by FVC % predicted as compared to placebo-treated patients. The distance walked in 6 minutes increased by a median of 15.0 meters for Myozyme-treated patients and decreased by a median of 7.5 meters for placebo-treated patients, indicating a statistically significant Myozyme treatment effect compared to placebo (p=0.0283). The % predicted FVC changed by a median of 0.0 for Myozyme-treated patients and decreased by a median of 3% for placebo-treated patients, indicating a statistically significant treatment effect (p=0.0026). The results are shown in Table 4.

Table 4: Change from baseline: efficacy outcomes in the placebo-controlled study

	Myozyme (N = 60)	Placebo (N = 30)
6-Minute Walk Test Distance (meters)
Pre-treatment Baseline	Mean ± s.d. Median	332.20 ± 126.69 360.0	317.93 ± 132.29 339.0
Week 78/Last Observation	Mean ± s.d. Median	357.85 ± 141.32 367.5	313.07 ± 144.69 307.0
Change from Baseline to Week 78/Last Observation*	Mean ± s.d Median

antihistamine, decongestant, and anticholinergic combination Oral

Class Name: antihistamine, decongestant, and anticholinergic combination (Oral route)

Commonly used brand name(s)

In the U.S.

• Allerx-D


• Dallergy


• Extendryl JR


• Extendryl SR


• Phenylephrine CM


• Rescon ER


• Stahist

Available Dosage Forms:

• Syrup


• Tablet, Extended Release


• Capsule, Extended Release


• Tablet


• Solution


• Suspension


• Tablet, Chewable

Uses For This Medicine

In November 2000, the Food and Drug Administration (FDA) issued a public health warning regarding phenylpropanolamine (PPA) due to the risk of hemorrhagic stroke. The FDA, supported by results of a research program, requested that manufacturers voluntarily discontinue marketing products that contain PPA and that consumers work with their healthcare providers to select alternative products.

Antihistamine, decongestant, and anticholinergic combinations are used to treat the nasal congestion (stuffy nose) and runny nose caused by allergies and/or the common cold.

Antihistamines work by preventing the effects of a substance called histamine, which is produced by the body. Histamine can cause itching, sneezing, runny nose, and watery eyes. The antihistamine contained in these combinations is chlorpheniramine.

The decongestants in these combinations, phenylephrine, and pseudoephedrine produce a narrowing of blood vessels. This leads to clearing of nasal congestion, but it may also cause an increase in blood pressure in patients who have high blood pressure.

Anticholinergics, such as atropine, hyoscyamine, methscopolamine, and scopolamine may help produce a drying effect in the nose and chest.

Some of these medicines are available without a prescription.

Do not give any over-the-counter (OTC) cough and cold medicine to a baby or child under 4 years of age. Using these medicines in very young children might cause serious or possibly life-threatening side effects .

Before Using This Medicine

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Very young children are usually more sensitive than adults to the effects of this medicine. Increases in blood pressure, nightmares or unusual excitement, nervousness, restlessness, or irritability may be more likely to occur in children. Also, when anticholinergics are given to children during hot weather, a rapid increase in body temperature may occur, which may lead to heat stroke. In infants and children, especially those with spastic paralysis or brain damage, this medicine may be especially likely to cause severe side effects.

Do not give any over-the-counter (OTC) cough and cold medicine to a baby or child under 4 years of age. Using these medicines in very young children might cause serious or possibly life-threatening side effects .

Geriatric

Confusion or memory loss, difficult and painful urination, dizziness, drowsiness, dryness of mouth, or convulsions (seizures) may be more likely to occur in the elderly, who are usually more sensitive than younger adults to the effects of this medicine. Also, nightmares or unusual excitement, nervousness, restlessness, or irritability may be more likely to occur in elderly patients. In addition, eye pain may occur, which may be a sign of glaucoma.

Pregnancy

For the individual ingredients of these combinations, the following apply:

• Antihistamines—Antihistamines have not been shown to cause problems in humans.


• Atropine—Studies on effects in pregnancy have not been done in humans. Atropine has not been shown to cause birth defects or other problems in animals.


• Hyoscyamine—Studies on effects in pregnancy have not been done in either humans or animals.


• Methscopolamine—Studies on effects in pregnancy have not been done in either humans or animals.


• Phenylephrine—Studies on birth defects have not been done in either humans or animals.


• Pseudoephedrine—Studies on birth defects have not been done in humans. Pseudoephedrine has not been shown to cause birth defects in animal studies. However, studies in animals have shown that pseudoephedrine causes a reduction in average weight, length, and rate of bone formation in the animal fetus.


• Scopolamine—Studies on effects in pregnancy have not been done in pregnant women. However, studies in animals at doses many times the human dose have shown that scopolamine causes a small increase in the number of fetal deaths.

Breast Feeding

Small amounts of antihistamines, decongestants, and anticholinergics may pass into the breast milk. Use is not recommended since this medicine may cause side effects, such as unusual excitement or irritability, in the nursing baby. Also, since this medicine tends to decrease the secretions of the body, it is possible that the flow of breast milk may be reduced in some women.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Potassium

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Brain damage in children or


• Down syndrome or


• Dryness of mouth (severe and continuing) or


• Enlarged prostate or


• Fever or


• Glaucoma or


• Intestinal blockage or other intestinal problems or


• Kidney disease or


• Liver disease or


• Lung disease or


• Mental or emotional problems or


• Myasthenia gravis or


• Toxemia of pregnancy or


• Urinary tract blockage or difficult urination—These medicines may make these conditions worse.

• Type 2 diabetes mellitus—The decongestant in this medicine may put diabetic patients at greater risk of having heart or blood vessel disease.

• Heart or blood vessel disease or


• High blood pressure—The decongestant and anticholinergic in this medicine may cause the blood pressure to increase and may also speed up the heart rate.

• Overactive thyroid—If the overactive thyroid has caused a fast heartbeat, the decongestant and anticholinergic in this medicine may cause the heart rate to speed up further.

Proper Use of This Medicine

Take this medicine only as directed. Do not take more of it and do not take it more often than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of side effects.

If this medicine irritates your stomach, you may take it with food or a glass of water or milk, to lessen the irritation.

For patients taking the extended-release capsule or extended-release tablet form of this medicine:

• Swallow the capsule or tablet whole.


• Do not crush, break, or chew before swallowing.


• If the capsule is too large to swallow, you may mix the contents of the capsule with applesauce, jelly, honey, or syrup and swallow without chewing.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For regular (short-acting) dosage forms (syrup, tablets, or chewable tablets):
  
  • For allergy and cold symptoms:
    
    • Adults and children 12 years of age and older—1 or 2 tablets or chewable tablets, or 1 to 2 teaspoonfuls of syrup every four to six hours.
    
    
    • Children 6 to 12 years of age—1 chewable tablet or 1 teaspoonful of syrup every four hours.
    
    
    • Children 4 to 6 years of age—Use and dose must be determined by your doctor.
    
    
    • Children and infants up to 4 years of age—Use is not recommended .
    
    
  
  


• For long-acting dosage forms (extended-release capsules or tablets):
  
  • For allergy and cold symptoms:
    
    • Adults and children 12 years of age and older—1 capsule or tablet every twelve hours.
    
    
    • Children 4 to 12 years of age—Use and dose must be determined by your doctor.
    
    
    • Children and infants up to 4 years of age—Use is not recommended .
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using This Medicine

Check with your doctor if your symptoms do not improve or become worse, or if you have a high fever

Before you have any skin tests for allergies, tell the doctor in charge that you are taking this medicine. The results of the test may be affected by the antihistamine in this medicine.

These medicines may make you sweat less, causing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking this medicine, since overheating may result in heat stroke. Also hot baths or saunas may make you dizzy or faint while you are taking this medicine.

The anticholinergic contained in this medicine may cause some people to have blurred vision. Make sure your vision is clear before you drive or do anything else that could be dangerous if you are not able to see well. These medicines may also cause your eyes to become more sensitive to light than they are normally. Wearing sunglasses may help lessen the discomfort from bright light.

These medicines may cause some people to become dizzy or drowsy. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

The decongestant in this medicine may cause some people to be nervous or restless or to have trouble in sleeping. If you have trouble in sleeping, take the last dose of this medicine for each day a few hours before bedtime. If you have any questions about this, check with your doctor.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.

This medicine may cause dryness of the mouth, nose, and throat. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

If you think you or someone else may have taken an overdose, get emergency help at once. Taking an overdose of this medicine or taking this medicine with alcohol or other CNS depressants may lead to unconsciousness and possibly death.

Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Get emergency help immediately if any of the following symptoms of overdose occur:

For pseudoephedrine only

• Unusual nervousness, restlessness, or excitement

• Clumsiness or unsteadiness


• convulsions (seizures)


• drowsiness (severe)


• dryness of mouth, nose, or throat (severe)


• fast heartbeat


• flushing or redness of face


• hallucinations (seeing, hearing, or feeling things that are not there)


• headache (continuing)


• shortness of breath or troubled breathing


• trouble in sleeping

Check with your doctor as soon as possible if any of the following side effects occur:

Rare

• Irregular or slow heartbeat


• mood or mental changes


• skin rash, hives, or itching


• sore throat and fever


• tightness in chest


• unusual bleeding or bruising


• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Drowsiness


• nervousness


• restlessness


• thickening of mucus


• trouble in sleeping

Less common - more common with high doses

• Blurred vision


• confusion


• difficult or painful urination


• dizziness


• dryness of mouth, nose, or throat


• fast or pounding heartbeat


• headache


• increased sweating


• loss of appetite


• nausea or vomiting


• nightmares


• ringing or buzzing in ears


• trembling


• unusual excitement, nervousness, restlessness, or irritability


• unusual paleness


• weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

The information contained in the Thomson Healthcare (Micromedex) products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Healthcare does not assume any responsibility or risk for your use of the Thomson Healthcare products.

Spiriva 18 microgram inhalation powder, hard capsule

1. Name Of The Medicinal Product

SPIRIVA^® 18 microgram, inhalation powder, hard capsule

2. Qualitative And Quantitative Composition

Each capsule contains 22.5 microgram tiotropium bromide monohydrate equivalent to 18 microgram tiotropium.

The delivered dose (the dose that leaves the mouthpiece of the HandiHaler^® device) is 10 microgram tiotropium.

Excipient: Lactose monohydrate

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Inhalation powder, hard capsule.

Light green hard capsules with the product code TI 01 and company logo printed on the capsule.

4. Clinical Particulars

4.1 Therapeutic Indications

Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD).

4.2 Posology And Method Of Administration

The recommended dosage of tiotropium bromide is inhalation of the contents of one capsule once daily with the HandiHaler device at the same time of day.

The recommended dose should not be exceeded.

Tiotropium bromide capsules must not be swallowed.

Tiotropium bromide should only be inhaled with the HandiHaler device.

Instructions for handling and use:

	Remember to carefully follow your doctor's instructions for using SPIRIVA. The HandiHaler is especially designed for SPIRIVA. You must not use it to take any other medication. You can use your HandiHaler for up to one year to take your medication.
	The HandiHaler 1 Dust cap 2 Mouthpiece 3 Base 4 Piercing button 5 Centre chamber
	1. To release the dust cap press the piercing button completely in and let go.
	2. Open the dust cap completely by pulling it upwards. Then open the mouthpiece by pulling it upwards.
	3. Remove a SPIRIVA capsule from the blister (only immediately before use) and place it in the centre chamber (5), as illustrated. It does not matter which way the capsule is placed in the chamber.
	4. Close the mouthpiece firmly until you hear a click, leaving the dust cap open.
	5. Hold the HandiHaler device with the mouthpiece upwards and press the piercing button completely in only once, and release. This makes holes in the capsule and allows the medication to be released when you breathe in.
	6. Breathe out completely. Important: Please avoid breathing into the mouthpiece at any time.
	7. Raise the HandiHaler to your mouth and close your lips tightly around the mouthpiece. Keep your head in an upright position and breathe in slowly and deeply but at a rate sufficient to hear or feel the capsule vibrate. Breathe in until your lungs are full; then hold your breath as long as comfortable and at the same time take the HandiHaler out of your mouth. Resume normal breathing. Repeat steps 6 and 7 once, in order to empty the capsule completely.
	8. Open the mouthpiece again. Tip out the used capsule and dispose. Close the mouthpiece and dust cap for storage of your HandiHaler device.

Cleaning your HandiHaler

Clean the HandiHaler once a month. Open the dust cap and mouthpiece. Then open the base by lifting the piercing button. Rinse the complete inhaler with warm water to remove any powder. Dry the HandiHaler thoroughly by tipping excess of water out on a paper towel and air-dry afterwards, leaving the dust cap, mouthpiece and base open. It takes 24 hours to air dry, so clean it right after you used it and it will be ready for your next dose. If needed, the outside of the mouthpiece may be cleaned with a moist but not wet tissue.

Blister handling

	A. Separate the blister strips by tearing along the perforation.
	B. Peel back foil (only immediately before use) using the tab until one capsule is fully visible. In case a second capsule is exposed to air inadvertently this capsule has to be discarded.
	C. Remove capsule.

SPIRIVA^® capsules contain only a small amount of powder so that the capsule is only partially filled.

Special Populations:

Geriatric patients can use tiotropium bromide at the recommended dose.

Renally impaired patients can use tiotropium bromide at the recommended dose. For patients with moderate to severe impairment (creatinine clearance

Hepatically impaired patients can use tiotropium bromide at the recommended dose (see 5.2 Pharmacokinetic properties).

Paediatric patients: Safety and effectiveness of tiotropium bromide inhalation powder in paediatric patients have not been established and therefore it should not be used in patients under 18 years of age.

4.3 Contraindications

Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to the excipient lactose monohydrate which contains milk protein.

4.4 Special Warnings And Precautions For Use

Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.

Immediate hypersensitivity reactions may occur after administration of tiotropium bromide inhalation powder.

Consistent with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. (see 4.8 undesirable effects)

Inhaled medicines may cause inhalation-induced bronchospasm.

As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance

Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately.

Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.

Tiotropium bromide should not be used more frequently than once daily (see section 4.9 Overdose).

SPIRIVA capsules contain 5.5 mg lactose monohydrate.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although no formal drug interaction studies have been performed, tiotropium bromide inhalation powder has been used concomitantly with other drugs without clinical evidence of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD.

The co-administration of tiotropium bromide with other anticholinergic-containing drugs has not been studied and is therefore not recommended.

4.6 Pregnancy And Lactation

For tiotropium bromide, no documented clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity associated with maternal toxicity (see section 5.3, Preclinical Safety Data). The potential risk for humans is unknown. SPIRIVA should therefore only be used during pregnancy when clearly indicated.

It is unknown whether tiotropium bromide is excreted in human breast milk. Despite studies in rodents which have demonstrated that excretion of tiotropium bromide in breast milk occurs only in small amounts, use of SPIRIVA is not recommended during breast-feeding. Tiotropium bromide is a long-acting compound. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with SPIRIVA should be made taking into account the benefit of breast-feeding to the child and the benefit of SPIRIVA therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness, blurred vision, or headache may influence the ability to drive and use machinery.

4.8 Undesirable Effects

a) General Description

Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA.

b) Table of Undesirable Effects

The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,149 patients) from 26 pooled placebo-controlled clinical trials with treatment periods ranging from four weeks to four years.

Frequency is defined using the following convention:

Very common (

MedDRA Preferred Term	Frequency
Metabolism and nutrition disorders
Dehydration	Not known*
Nervous system disorders
Dizziness	Uncommon
Headache	Uncommon
Taste disorders	Uncommon
Insomnia	Rare
Eye disorders
Vision blurred	Uncommon
Glaucoma	Rare
Intraocular pressure increased	Rare
Cardiac disorders
Atrial fibrillation	Uncommon
Supraventricular tachycardia	Rare
Tachycardia	Rare
Palpitations	Rare
Respiratory, thoracic and mediastinal disorders
Pharyngitis	Uncommon
Dysphonia	Uncommon
Cough	Uncommon
Bronchospasm	Rare
Epistaxis	Rare
Laryngitis	Rare
Sinusitis	Rare
Gastrointestinal Disorders
Dry Mouth	Common
Stomatitis	Uncommon
Gastrooesophageal reflux disease	Uncommon
Constipation	Uncommon
Nausea	Uncommon
Intestinal obstruction, including ileus paralytic	Rare
Gingivitis	Rare
Glossitis	Rare
Oropharyngeal candidiasis	Rare
Dysphagia	Rare
Dental caries	Not known*
Skin and subcutaneous tissue disorders, Immune system disorders :
Rash	Uncommon
Urticaria	Rare
Pruritus	Rare
Hypersensitivity (including immediate reactions)	Rare
Angioneurotic oedema	Not known*
Skin infection, skin ulcer	Not known*
Dry skin	Not known*
Musculoskeletal and connective tissue disorders
Joint swelling	Not known*
Renal and Urinary Disorders
Dysuria	Uncommon
Urinary retention	Uncommon
Urinary tract infection	Rare

*no events attributed to tiotropium in 9,149 tiotropium treated patients; however, events are considered adverse drug reactions associated with tiotropium

c) Information Characterising Individual Serious and/or Frequently Occurring Undesirable Effects

In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients. In 26 clinical trials, dry mouth led to discontinuation in 18 of 9,149 tiotropium treated patients (0.2%).

Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.

Additional information on special populations

An increase in anticholinergic effects may occur with increasing age.

4.9 Overdose

High doses of tiotropium bromide may lead to anticholinergic signs and symptoms.

However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 microgram tiotropium bromide in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following 7 day dosing of up to 170 microgram tiotropium bromide in healthy volunteers. In a multiple dose study in COPD patients with a maximum daily dose of 43 microgram tiotropium bromide over four weeks no significant undesirable effects have been observed.

Acute intoxication by inadvertent oral ingestion of tiotropium bromide capsules is unlikely due to low oral bioavailability.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anticholinergics

ATC code: R03B B04

Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has similar affinity to the subtypes of muscarinic receptors, M₁ to M₅. In the airways, tiotropium bromide competitively and reversibly antagonises the M₃ receptors, resulting in relaxation. The effect was dose dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M₃ receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur. The bronchodilation is primarily a local effect (on the airways), not a systemic one.

Dissociation from M₂-receptors is faster than from M₃, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M₃ over M₂. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.

Electrophysiology: In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.

The clinical development programme included four one-year and two six-month randomised, double-blind studies in 2663 patients (1308 receiving tiotropium bromide). The one-year programme consisted of two placebo-controlled trials and two trials with an active control (ipratropium). The two six-month trials were both, salmeterol and placebo controlled. These studies included lung function and health outcome measures of dyspnea, exacerbations and health-related quality of life.

In the aforementioned studies, tiotropium bromide, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second, FEV₁ and forced vital capacity, FVC) within 30 minutes following the first dose which was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. Tiotropium bromide significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The bronchodilator effects of tiotropium bromide were maintained throughout the one-year period of administration with no evidence of tolerance.

A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether the drug was administered in the morning or in the evening.

The following health outcome effect was demonstrated in the long term (6-month and one-year) trials:

Tiotropium bromide significantly improved dyspnea (as evaluated using the Transition Dyspnea Index.). This improvement was maintained throughout the treatment period.

The impact of improvements in dyspnea on exercise tolerance was investigated in two randomised, double-blind, placebo-controlled trials in 433 patients with moderate to severe COPD. In these trials, six weeks of treatment with SPIRIVA significantly improved symptom-limited exercise endurance time during cycle ergometry at 75% of maximal work capacity by 19.7% (Trial A: 640 seconds with SPIRIVA vs. 535 seconds with placebo, compared with a pre-treatment baseline of 492 seconds) and 28.3% (Trial B: 741 seconds with SPIRIVA vs. 577 seconds with placebo, compared with a pre-treatment baseline of 537 seconds).

In a randomized, double-blind, placebo controlled trial of 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the proportion of patients who experienced exacerbations of COPD (32.2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In addition, 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056). The number of hospitalizations due to COPD was reduced by 30% (0.25 to 0.18 events per patient year of exposure).

In a 9-month, randomized, double-blind, placebo-controlled clinical trial of 492 patients, SPIRIVA improved health-related quality of life as determined by the St. George's Respiratory Questionnaire (SGRQ) total score. The proportion of patients treated with SPIRIVA which achieved a meaningful improvement in the SGRQ total score (i.e.> 4 units) was 10.9% higher compared with placebo (59.1% in the SPIRIVA groups vs. 48.2% in the placebo group (p=0.029). The mean difference between the groups was 4.19 units (p=0.001; confidence interval: 1.69 – 6.68). The improvements of the subdomains of the SGRQ-score were 8.19 units for “symptoms”, 3.91 units for “activity” and 3.61 units for “impact on daily life”. The improvements of all these separate subdomians were statistically significant.

In a 4-year, randomised, double-blind, placebo-controlled clinical trial of 5,993 randomised patients (3,006 receiving placebo and 2,987 receiving Spiriva), the improvement in FEV₁ resulting from Spiriva, compared with placebo, remained constant throughout 4 years. A higher proportion of patients completed ₁ compared to placebo was similar between Spiriva and placebo. During treatment, there was a 16% reduction in the risk of death. The incidence rate of death was 4.79 per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the tiotropium group (hazard ratio (tiotropium/placebo) = 0.84, 95% CI = 0.73, 0.97). Treatment with tiotropium reduced the risk of respiratory failure (as recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).

5.2 Pharmacokinetic Properties

a) General Introduction

Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.

b) General Characteristics of the Active Substance after Administration of the Medicinal Product

Absorption: Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) and from in-vitro experiments that tiotropium bromide is poorly absorbed from the gastrointestinal tract (10-15%). Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Maximum tiotropium bromide plasma concentrations were observed five minutes after inhalation. Food is not expected to influence the absorption of this quaternary ammonium compound.

Distribution: The drug is bound by 72% to plasma proteins and shows a volume of distribution of 32 L/kg. At steady state, tiotropium bromide plasma levels in COPD patients at peak were 17 – 19 pg/ml when measured 5 minutes after dry powder inhalation of a 18 microgram dose and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 3-4 pg/ml. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.

Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. The ester tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on muscarinic receptors. In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (< 20% of dose after intravenous administration) is metabolised by cytochrome P450 (CYP) dependent oxidation and subsequent glutathion conjugation to a variety of Phase II-metabolites.

In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP 2D6 and 3A4 are involved in metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Elimination: The terminal elimination half-life of tiotropium bromide is between 5 and 6 days following inhalation. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers with an interindividual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation urinary excretion is 14% of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium bromide exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2-3 weeks with no accumulation thereafter.

Linearity / Nonlinearity: Tiotropium bromide demonstrates linear pharmacokinetics in the therapeutic range after both intravenous administration and dry powder inhalation.

c) Characteristics in Patients

Geriatric Patients: As expected for all predominantly renally excreted drugs, advanced age was associated with a decrease of tiotropium bromide renal clearance (326 mL/min in COPD patients < 58 years to 163 mL/min in COPD patients> 70 years) which may be explained by decreased renal function. Tiotropium bromide excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however plasma concentrations did not change significantly with advancing age within COPD patients if compared to inter- and intraindividual variability (43% increase in AUC_0-4h after dry powder inhalation.

Renally Impaired Patients: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with increased plasma drug concentrations and reduced renal drug clearance after both intravenous infusion and dry powder inhalations. Mild renal impairment (CL_CR 50-80 ml/min) which is often seen in elderly patients increased tiotropium bromide plasma concentrations slightly (39% increase in AUC_0-4h after intravenous infusion). In COPD patients with moderate to severe renal impairment (CL_CR < 50 ml/min) the intravenous administration of tiotropium bromide resulted in doubling of the plasma concentrations (82% increase in AUC_0-4h), which was confirmed by plasma concentrations after dry powder inhalation.

Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on tiotropium bromide pharmacokinetics. Tiotropium bromide is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.

Paediatric Patients: See 4.2 Posology and Method of Administration

d) Pharmacokinetic / Pharmacodynamic Relationship(s)

There is no direct relationship between pharmacokinetics and pharmacodynamics.

5.3 Preclinical Safety Data

Many effects observed in conventional studies of safety pharmacology, repeated dose toxicity, and reproductive toxicity could be explained by the anticholinergic properties of tiotropium bromide. Typically in animals reduced food consumption, inhibited body weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate were observed. Other relevant effects noted in repeated dose toxicity studies were: mild irritancy of the respiratory tract in rats and mice evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder in rats.

Harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. Tiotropium bromide was not teratogenic in rats or rabbits. The respiratory (irritation) and urogenital (prostatitis) changes and reproductive toxicity were observed at local or systemic exposures more than five-fold the therapeutic exposure. Studies on genotoxicity and carcinogenic potential revealed no special hazard for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate (which contains milk protein)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

After first opening of the blister: 9 days

Discard the HandiHaler device 12 months after first use.

6.4 Special Precautions For Storage

Do not store above 25°C

Do not freeze

6.5 Nature And Contents Of Container

Aluminium / PVC / Aluminium blister strips containing 10 capsules

The HandiHaler is a single dose inhalation device made from plastic materials (ABS) and stainless steel.

Package sizes and devices supplied:

• Cardboard box containing 30 capsules (3 blister strips)

• Cardboard box containing 60 capsules (6 blister strips)

• Cardboard box containing 90 capsules (9 blister strips)

• Cardboard box containing HandiHaler device

• Cardboard box containing HandiHaler device and 10 capsules (1 blister strip)

• Cardboard box containing HandiHaler device and 30 capsules (3 blister strips)

• Hospital pack: Bundle pack containing 5 cardboard boxes of 30 capsules plus HandiHaler device

• Hospital pack: Bundle pack containing 5 cardboard boxes of 60 capsules

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Straße 173

D-55216 Ingelheim am Rhein

Germany

8. Marketing Authorisation Number(S)

PL 14598/0062

9. Date Of First Authorisation/Renewal Of The Authorisation

09/10/2006

10. Date Of Revision Of The Text

March 2010

LEGAL CATEGORY

POM