NEXIUM®
(esomeprazole magnesium trihydrate)
20 and 40 mg delayed release tablets
THERAPEUTIC CLASSIFICATION
H+, K+-ATPase
Inhibitor
NOTE: When used in combination with amoxicillin and clarithromycin, the Product
Monographs for those agents must be consulted and followed.
ACTIONS AND CLINICAL PHARMACOLOGY
NEXIUM (esomeprazole magnesium trihydrate) delayed release tablets contain esomeprazole (the S-isomer of omeprazole). Esomeprazole is acid labile and therefore is administered orally as enteric-coated granules compressed into a tablet.
Esomeprazole magnesium (a substituted benzimidazole), reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the gastric enzyme H+, K+-ATPase (the proton pump) which is responsible for acid secretion by the parietal cells of the stomach.
Pharmacokinetics
Absorption of esomeprazole in healthy subjects results in peak plasma levels occurring 1 to 2 hours after dosing. The systemic bioavailability is 64% after a single 40 mg dose and 89% after repeated once daily oral administration (40 mg for 5 days). The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% protein bound and optically stable in vivo, with negligible inversion to the other isomer.
A pharmacokinetic profile of esomeprazole was studied in 36 patients with symptomatic GERD after repeated once daily administration of 20 mg and 40 mg (Table 1).
| TABLE 1: Pharmacokinetic parameters of esomeprazole after oral administration for 5 days. Mean (%CV) | ||
| Parameters |
NEXIUM
40 mg
|
NEXIUM
20 mg
|
| AUC(tot) (mmol*h/L) |
12.6
(42%)
|
4.2
(59%)
|
| Cmax (mmol/L) |
4.7
(37%)
|
2.1
(45%)
|
| Tmax (h) |
1.6
(50%)
|
1.6
(86%)
|
| t1/2 (h) |
1.5
(32%)
|
1.2
(37%)
|
| Values represent geometric mean except the Tmax, which is the arithmetic mean. | ||
Food intake delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Pharmacokinetics in combination with antibiotics
Interactions between esomeprazole
(20 mg b.i.d.), amoxicillin (1 g b.i.d.) and clarithromycin (500 mg b.i.d.),
were evaluated in a 4- way cross-over study (each study period was 7 days).
When given as the triple combination, the bioavailability (AUC and Cmax)
of amoxicillin and clarithromycin were not significantly changed in healthy
volunteers, compared with either drug given alone. The AUC and Cmax
of the 14-hydroxyclarithromycin metabolite were both increased by 53% during
dosing with the triple combination, compared to values following dosing with
clarithromycin alone. There were also significant increases in the AUC (two-fold
increase) and Cmax (39%) values for esomeprazole during concomitant
administration with the antibiotic drugs, compared with esomeprazole alone.
Metabolism
Esomeprazole is completely metabolized by the cytochrome P-450 system, mainly
in the liver (via CYP 2C19 and CYP 3A4). The major metabolites of esomeprazole
(hydroxy and desmethyl metabolites) have no effect on gastric acid secretion.
The CYP 2C19 isozyme, which is involved in the metabolism of all available proton
pump inhibitors, exhibits polymorphism. Some 3% of Caucasians and 15-20% of
Asians lack CYP 2C19 and are termed "poor metabolizers." At steady state (40
mg for 5 days), the ratio of AUC in poor metabolizers to AUC in the rest of
the population is approximately 2. Dosage adjustment of NEXIUM based on CYP
2C19 status is not necessary.
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in urine with the remainder recovered in feces. Less than 1% of the parent drug is found in urine. Total recovery from urine and feces is 92 to 96% within 48 hours of a single oral dose.
Pharmacodynamics
Esomeprazole accumulates in the acidic environment of the parietal cells after absorption, where it is converted into the active form. This active sulphenamide specifically binds the H+, K+-ATPase (proton pump), to block the final step in acid production, thus reducing gastric acidity. Esomeprazole is effective in the inhibition of both basal acid secretion and stimulated acid secretion.
In healthy male subjects (N=12), repeated administration with 20 mg NEXIUM once daily for 5 days, decreased mean peak acid output after pentagastrin stimulation by 90% when measured 6 to 7 hours after dosing.
The effect of antisecretory therapy can be predicted from the duration of suppression of intragastric acidity to above pH 4.0 achieved by each drug regimen, and the length of treatment.
The antisecretory activity of esomeprazole magnesium was studied in patients with symptomatic gastroesophageal reflux disease. NEXIUM 20 and 40 mg tablets were administered over 5 days and the proportion of time over 24 hours was assessed on Day 5, as shown in the following table:
| TABLE 2: Effect on Intragastric pH on Days 5 (N=36) | ||
| Parameter |
NEXIUM
40 mg
|
NEXIUM
20 mg
|
| % time gastric pH > 4* (hours) |
70%
** (16.8 hours)
|
53%
(12.7 hours)
|
| coefficient of variation |
26%
|
37%
|
| Median 24 hour pH |
4.9
**
|
4.1
|
| coefficient of variation |
16%
|
27%
|
| * Gastric
pH was measued over a 24-hr period ** p< 0.01 NEXIUM 4.0 mg vs. NEXIUM 20 mg |
||
Eradication of Helicobacter pylori
Infection with Helicobacter pylori (H. pylori) is associated with peptic ulcer disease and is a major factor in the development of gastritis. Approximately 90 to 100% of patients with duodenal ulcers, and 80% of patients with gastric ulcer, are infected with H. pylori. Treatment with NEXIUM alone has been shown to suppress, but not eradicate H. pylori.
Eradication of H. pylori with triple therapy consisting of NEXIUM and clarithromycin/ amoxicillin for seven days is associated with healing and improvement of symptoms of duodenal ulcers.
INDICATIONS AND CLINICAL USE
NEXIUM (esomeprazole magnesium trihydrate) tablets are indicated for treatment of conditions where a reduction of gastric acid secretion is required such as: reflux esophagitis, maintenance treatment of patients with reflux esophagitis, symptomatic gastroesophageal reflux disease (i.e. heartburn and regurgitation), and H. pylori eradication.
NEXIUM, in combination with clarithromycin and amoxicillin, is indicated for the treatment of patients with duodenal ulcer disease associated with Helicobacter pylori infection to eradicate the H. pylori and heal ulcers. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
CONTRAINDICATIONS
Hypersensitivity to esomeprazole, substituted benzimidazoles or any of the components of this medication (see PHARMACEUTICAL INFORMATION).
When used for eradication of Helicobacter pylori, the contraindications for amoxicillin and clarithromycin as found in the corresponding Product Monographs should be taken into consideration.
WARNINGS
In the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and/or when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.
Use in Pregnancy
The safety of NEXIUM (esomeprazole magnesium trihydrate) in pregnancy has not been established. NEXIUM tablets should not be administered to pregnant women unless the expected benefits outweigh the potential risks.
Nursing Mothers
It has not been investigated whether or not esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore, NEXIUM tablets should not be given to nursing mothers unless its use is considered essential.
Use in Children
The safety and effectiveness of NEXIUM tablets in children have not yet been established.
PRECAUTIONS
Use in the Elderly
The metabolism of NEXIUM (esomeprazole magnesium trihydrate) is not significantly changed in elderly subjects. Following repeated oral dosing with 40 mg NEXIUM in healthy elderly subjects (6 males, 8 females; 71 to 80 years of age), AUC and Cmax values measured were similar to those previously measured in young GERD patients (ratio of AUC values in elderly vs. GERD subjects: 1.25; ratio of Cmax values: 1.18). Therefore, dose adjustment is not required in the elderly.
Gender
The AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Dosage adjustment based on gender is not necessary.
Poor Metabolizers
The CYP 2C19 and CYP 3A4 isozymes are responsible for metabolism of esomeprazole. CYP 2C19, which is involved in the metabolism of all available proton pump inhibitors, exhibits polymorphism. Approximately 3% of Caucasians and 15-20% of Asians lack CYP 2C19 and are termed "poor metabolizers." At steady state, the ratio of AUC in poor metabolizers to AUC in the rest of the population is approximately 2. Dosage adjustment of NEXIUM based on CYP 2C19 status is not necessary.
Patients with Hepatic Insufficiency
The metabolism of esomeprazole magnesium in patients with mild to moderate liver dysfunction (Child Pugh Class A or B), is similar to that in patients with symptoms of GERD with normal liver function. Metabolism of esomeprazole is decreased in patients with severe liver dysfunction (Child Pugh Class C) resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. The plasma elimination half-life in patients with severe liver dysfunction is still very short (3 hours) relative to the dosing interval (24 hours). Esomeprazole and its major metabolites do not show any tendency to accumulate with once-daily dosing. Dose adjustment is not required in patients with mild to moderate liver impairment. A daily dose of 20 mg in patients with severe liver disease should not, as a rule, be exceeded (see DOSAGE AND ADMINISTRATION).
Patients with Renal Insufficiency
Since the kidney is responsible for the excretion of metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Esomeprazole is extensively protein-bound and is, therefore, not expected to be readily dialyzable. Dose adjustment is not required in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).
Carcinogenicity
Long-term toxicity studies of omeprazole, revealed the gastric mucosa as the target organ. The carcinogenic potential of esomeprazole was assessed using omeprazole studies. In the rat carcinogenicity study (24 months), ECL-cell carcinoids were found in some animals treated with 14-140 mg/kg/day for their normal life span. ECL-cell carcinoids were seen in a background of ECL-cell hyperplasia. No ECL-cell carcinoids were identified in the carcinogenicity study in mice or in long-term (up to 7 years) general toxicity studies in dogs.
A vast number of studies have revealed that pronounced and sustained hypergastrinemia is the mechanism behind the development of the gastric ECL-cell carcinoids in the rat. Such ECL carcinoids have been seen in rats after life-long treatment with other inhibitors of acid secretion such as H2-receptor blockers and other proton pump inhibitors. Partial fundectomy in rats results in hypergastrinemia and gastric ECL-cell carcinoids in the remaining part of the fundic mucosa, towards the end of the rats' life span.
Treatment with NEXIUM for up to 1 year in more than 800 patients has not resulted in any significant pathological changes in the gastric oxyntic endocrine cells. Short-term treatment and long-term treatment with the racemate, omeprazole, capsules in a limited number of patients for up to 11 years have not resulted in any significant pathological changes in gastric oxyntic endocrine cells.
During treatment with all antisecretory drugs serum gastrin increases in response to the decreased acid secretion. The effect of NEXIUM on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months (daily doses of either 20 or 40 mg). The mean fasting gastrin level increased in a dose- related manner. This increase reached a plateau (approximately 100 pg/mL) within two to three months of therapy and returned to baseline levels (approximately 30-40 pg/mL) within four weeks after discontinuation of therapy.
Drug Interactions
Esomeprazole magnesium is metabolized by the cytochrome P-450 system (CYP), mainly in the liver, through CYP 2C19 and CYP 3A4. There are no clinically significant interactions between esomeprazole and diazepam, phenytoin, warfarin, quinidine or cisapride.
Diazepam, Warfarin and Phenytoin
Diazepam
Concomitant administration of NEXIUM (30 mg once daily for 5 days) resulted
in a 45% decrease in the clearance of diazepam in healthy male volunteers. Studies
in females have not been conducted. Increased levels of diazepam were seen some
12 hours after dosing and later when the plasma levels of diazepam were below
its therapeutic range. Therefore, this interaction is unlikely to be of clinical
significance.
Warfarin
Concomitant administration of 40 mg NEXIUM (once daily for 3 weeks) to male
and female patients on stable anticoagulation therapy with warfarin, resulted
in a 13% increase in trough plasma levels of R-warfarin (the less potent enantiomer)
while that of S-warfarin was unchanged. Coagulation times were stable throughout
the entire study period. No clinically significant interaction was observed.
Phenytoin
Concomitant administration of 40 mg NEXIUM (once daily for 2 weeks) to male
and female epileptic patients stabilized on phenytoin, resulted in a 13% increase
in trough plasma levels of phenytoin. This minor interaction is unlikely to
be of clinical relevance as dose reduction was not required in any patient nor
was the profile and frequency of adverse events affected.
Results from a range of interaction studies with NEXIUM versus other drugs indicate that daily doses of 40 mg NEXIUM, given for 5 to 21 days in male and/or female subjects, has no clinically relevant interactions with CYP 1A2 (caffeine), CYP 2C9 (S-warfarin), and CYP 3A (quinidine, estradiol and cisapride).
ADVERSE REACTIONS
NEXIUM (esomeprazole magnesium trihydrate) is well-tolerated. Most adverse events have been mild and transient, showing no consistent relationship with treatment. Adverse events have been recorded during controlled clinical investigations in 6808 patients exposed to NEXIUM. An additional 1198 subjects/patients were exposed to NEXIUM in Phase I studies. Among events which occurred with a frequency of >1% in clinical studies, only headache, diarrhea, flatulence, abdominal pain, nausea, vomiting, dizziness and dry mouth are thought to be associated with the use of NEXIUM.
The following adverse events, irrespective of causal relationship, were reported (at a rate of more than 1%) in controlled short-term (up to 8 weeks) clinical trials involving 5668 patients:
| TABLE 3: Percentage of adverse events, irrespective of causal relationship, reported (at a rate of more than 1%) for patients in short-term clinical trials (up to 8 weeks) treated with NEXIUM. | |||
|
All
studies
|
Placebo
controlled studies
|
||
| Adverse Event |
NEXIUM
(20 & 40 mg) n=5668 (%) |
NEXIUM
(20 & 40 mg) n=470 (%) |
Placebo
n=240 (%) |
| Headache |
8.4
|
6.6
|
7.5
|
| Diarrhea |
5.7
|
5.7
|
4.2
|
| Respiratory infection |
3.8
|
1.9
|
3.8
|
| Abdominal pain |
3.6
|
5.7
|
2.5
|
| Nausea |
3.5
|
5.1
|
5.4
|
| Flatulence |
3.3
|
3.2
|
-
|
| Gastritis |
2.1
|
-
|
-
|
| Sinusitis |
1.7
|
2.8
|
2.5
|
| Constipation |
1.6
|
1.7
|
1.3
|
| Vomiting |
1.4
|
1.1
|
1.7
|
| Mouth dry |
1.3
|
1.3
|
-
|
| Pharyngitis |
1.3
|
0.4
|
1.3
|
| Dizziness |
1.2
|
0.9
|
1.7
|
| Viral infection |
1.1
|
-
|
0.4
|
In clinical trials up to 6 months' duration, the following adverse events were reported.
| TABLE 4: Percentage of adverse events, irrespective of causal relationship, reported (at a rate of more than 3%) for patients in clinical trials up to 6 months' duration treated with NEXIUM. | ||
| Adverse Event |
NEXIUM
(20 & 40 mg) n=519 (%) |
NEXIUM
(20 & 40 mg) n=169 (%) |
| Respiratory infection |
8.5
|
3.0
|
| Diarrhea |
6.7
|
3.0
|
| Headache |
6.6
|
4.1
|
| Gastritis/gastritis aggravated* |
6.2
|
5.3
|
| Flatulence |
5.0
|
1.8
|
| Nausea/nausea aggravated |
4.8
|
2.4
|
| Sinusitis |
4.2
|
1.8
|
| Abdominal pain |
3.7
|
2.4
|
| Accident and/or injury |
3.7
|
1.8
|
| Infection viral |
3.7
|
1.8
|
| Vomiting/vomiting aggravated |
3.3
|
1.2
|
| * endoscopic assessment | ||
Additionally, the following adverse events (irrespective of causality) were each reported at a rate of >1% with NEXIUM in these same long-term studies (N=519): rash, fracture, hernia, dizziness, duodenitis, dyspepsia, epigastric pain, serum gastrin increased, gastroenteritis, GI mucosal discoloration, esophageal disorder, tooth disorder, SGPT increased, hypertension, coughing, rhinitis, anemia, benign GI neoplasm, back pain, chest pain, and fatigue.
Clinical experience for up to one year in over 800 patients with doses of NEXIUM of 40 mg have shown a similar adverse event pattern to that seen in short-term trials. In addition to the adverse events listed above, the following adverse events were reported (at a rate of more than 1%), irrespective of causal relationship (mean duration of treatment = 294 days): accident/injury (7.6%), pain (4.3%), urinary tract infection (3.7%), bronchitis (3.6%), arthralgia (2.9%), hypertension (2.6%), allergy (2.1%), insomnia (2.1%), hypercholesterolemia (2.0%), anxiety (1.7%), gastroesophageal reflux (1.6%), fever (1.5%), ear infection (1.5%), flu-like disorder (1.4%), myalgia (1.2%), arthropathy (1.1%), dyspnea (1.1%), overdose (1.1%).
Events reported less frequently in either short- or long-term studies that have been associated with the use of NEXIUM include dermatitis, pruritus, and urticaria.
H. pylori Eradication Combination Therapy
In clinical studies, a total of 446 patients received NEXIUM in combination with amoxicillin and clarithromycin for 7 days. The following adverse events were reported (at a rate of more than 1%), irrespective of causal relationship: diarrhea (21.5%), taste perversion (12.6%), headache (3.6%), dry mouth (3.4%), SGPT increased (1.8%), flatulence (1.6%), nausea (1.3%), stomatitis (1.3%), vomiting (1.1%) and pharyngitis (1.1%). However, it should be noted that taste perversion is commonly associated with clarithromycin treatment and diarrhea is commonly associated with antibiotic treatment. When NEXIUM is used in combination with amoxicillin and clarithromycin, the Product Monographs for those agents must be consulted and followed.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
No information is available on the effects of higher doses in man, and specific recommendations for treatment cannot be given. Data are limited but single doses of 80 mg NEXIUM (esomeprazole magnesium trihydrate) were uneventful. No specific antidote is known. Esomeprazole is extensively protein-bound and is therefore not readily dialyzable. Treatment should be symptomatic and general supportive measures should be utilized.
The maximum non-lethal oral dose in male and female rats ranged from 240 to 480 mg/kg (see TOXICOLOGY).
When used in combination with antibiotics, the Prescribing Information/Product Monograph for those antibiotics should be consulted.
DOSAGE AND ADMINISTRATION
The tablets should be swallowed whole with sufficient water. The tablets may also be dispersed in half a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
Treatment of Conditions where a Reduction of Gastric Acid Secretion is Required
Reflux Esophagitis
The recommended adult dose in patients with reflux esophagitis is 40 mg NEXIUM
once daily for 4 to 8 weeks in order to optimize the healing rate and symptom
resolution. Healing occurs in the majority of patients within 4 weeks. Sustained
freedom from symptoms is achieved rapidly for most patients. An additional 4
weeks of treatment is recommended for patients in whom esophagitis has not healed
or who have persistent symptoms.
Maintenance of Healing
of Erosive Esophagitis
For the long-term treatment of patients whose reflux esophagitis has been healed
with acid suppression therapy, the recommended adult dose is 20 mg NEXIUM once
daily. Controlled studies do not extend beyond 6 months.
Symptomatic Gastroesophageal
Reflux Disease
In patients with heartburn and/or acid regurgitation, without esophagitis, the
recommended adult dose is 20 mg NEXIUM once daily for 2 to 4 weeks. If symptom
control is not achieved after 4 weeks of treatment, further investigation is
recommended.
Helicobacter pylori Eradication
In patients with
H. pylori-associated active duodenal ulcer
The recommended dose is NEXIUM 20 mg, amoxicillin 1000 mg and clarithromycin
500 mg, all twice daily for seven days. No further treatment with NEXIUM is
required to ensure healing and/or symptom control. This dosing regimen can also
be known as
NEXIUM 1-2-3 A™.
In patients with a history
of duodenal ulcer
The recommended dose is NEXIUM 20 mg, amoxicillin 1000 mg and clarithromycin
500 mg, all twice daily for seven days. This dosing regimen can also be known
as NEXIUM 1-2-3 A™. Eradication of H. pylori has been shown to reduce
the risk of duodenal ulcer recurrence.
Special Populations
When used in combination with amoxicillin and clarithromycin, please refer to the Product Monographs of these drugs for prescribing information regarding Contraindications, Warnings and Dosing (in elderly and patients with renal and hepatic insufficiency).
Patients with Renal Insufficiency: No dose adjustment is required (see PRECAUTIONS).
Patients with Hepatic Insufficiency: No dose adjustment is required for patients with mild to moderate hepatic impairment. The daily doses of 20 mg in patients with severe hepatic impairment should not, as a rule, be exceeded (see PRECAUTIONS).
Elderly Patients: No dose adjustment is required (see PRECAUTIONS).
PHARMACEUTICAL INFORMATION
Drug Substance
| Proper Name: | esomeprazole magnesium trihydrate |
| Chemical Name: | Di-(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H- benzimidazole magnesium trihydrate |
| Empirical Formula: | C34H36N6O6S2Mg·3H2O |
 |
|
| Molecular Weight: | 767.2
g/mol (trihydrate) 713.1 g/mol (anhydrous basis) |
| Description: | Esomeprazole
magnesium is a white to slightly coloured crystalline powder, containing 3 water molecules of hydration. The solubility in water is 0.3 mg/mL, and the solubility in methanol is initially high, but followed by precipitation of a crystalline dihydrate. The pKa of the benzimidazole (omeprazole base) is 8.8, and that of the pyridinium ion, 4.0. |
| Composition | |
| Active: | esomeprazole magnesium trihydrate |
| mg/tablet | 22.3 (corresponds
to 20 mg esomeprazole/tablet) 44.5 (corresponds to 40 mg esomeprazole/tablet) |
| Nonmedicinal: |
cellulose microcrystalline crospovidone glycerol monostearate hydroxypropyl cellulose hypromellose, iron oxide magnesium stearate methacrylic acid ethylacrylate copolymer polyethylene glycol polysorbate synthetic paraffin sodium stearyl fumarate sugar spheres talc titanium dioxide triethyl citrate |
Stability and Storage Recommendations
NEXIUM (esomeprazole magnesium trihydrate) tablets are moisture-sensitive and are therefore provided in blister compliance packages suitable for direct distribution to the patient. Store in a dry place at controlled room temperature (15-30°C).
AVAILABILITY OF DOSAGE FORMS
Esomeprazole is acid labile and therefore is administered orally as enteric-coated granules of the Multiple Unit Pellet System (MUPS™) tablet. The MUPS tablet consists of many enteric-coated granules compressed into a tablet.
NEXIUM (esomeprazole magnesium trihydrate) 20 mg tablets are
light pink, oblong and biconvex, engraved with "20 mg" on one side and 
on the other side. NEXIUM (esomeprazole magnesium trihydrate) 40 mg tablets
are pink, oblong and biconvex, engraved with "40 mg" on one side and 
on the other side.
The 20 and 40 mg tablets are provided in press-through blister compliance strips in cartons of 14, 28, or 56 and in HDPE bottles of 100 tablets.
Information for the patient is provided as a package insert in the compliance packages.
Full Product Monograph available on request.
AstraZeneca Canada Inc.
1004 Middlegate Road,
Mississauga, Ontario L4Y 1M4
Nexium® is a trademark of AstraZeneca AB, used under license by AstraZeneca Canada Inc.
Nexium 1-2-3 A™ is a trademark of AstraZeneca AB, used under license by AstraZeneca Canada Inc.
MUPS™ is a trademark of AstraZeneca AB, used under license by AstraZeneca Canada Inc.
 |
 |
|
 |
||
The AstraZeneca logo is a trademark of AstraZeneca PLC and is used under license by AstraZeneca Canada Inc.
CLICK HERE FOR LOSEC PI