Nimbus

Nimbus accuhaler 100, 250 or 500 contains Salmeterol (Nimbus) 50 mcg (as xinafoate) and Fluticasone (Nimbus) propionate 100, 250 or 500 mcg, respectively.

Nimbus accuhaler is a moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters.

Nimbus accuhaler also contains lactose (which contains milk protein) as an excipient.

Nimbus Evohaler: Each single actuation of Nimbus evohaler 50, 125 or 250 provides Salmeterol (Nimbus) xinafoate equivalent to Salmeterol (Nimbus) 25 mcg and Fluticasone (Nimbus) propionate 50, 125 or 250 mcg, respectively.

Nimbus evohaler also contains HFA134a as an excipient.

Nimbus evohaler comprises a suspension of Salmeterol (Nimbus) xinafoate and Fluticasone (Nimbus) propionate in the non-chlorofluoro carbon (CFC) propellant HFA 134a. The suspension is contained in an aluminium alloy can sealed with a metering valve. The canisters are fitted into plastic actuators incorporating an atomising orifice and fitted with dust caps.

The canister has a dose counter attached to it, which shows how many actuations of medicine are left. The number will show through a window in the back of the plastic actuator.

Treatment of Asthma

Nimbus is indicated for the treatment of asthma in patients aged 4 years and older.

LABA, such as Salmeterol (Nimbus), one of the active ingredients in Nimbus, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Nimbus for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Nimbus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Nimbus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use

Nimbus is NOT indicated for the relief of acute bronchospasm.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease

Nimbus 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Nimbus 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Nimbus 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength Nimbus 500/50 over Nimbus 250/50 has not been demonstrated.

Important Limitation of Use

Nimbus is NOT indicated for the relief of acute bronchospasm.

Fluticasone (Nimbus) and Salmeterol (Nimbus) is a combination of two medicines that are used to help control the symptoms of asthma and improve breathing. It is used when a patient's asthma has not been controlled sufficiently on other asthma medicines, or when a patient's condition is so severe that more than one medicine is needed every day. Fluticasone (Nimbus) and Salmeterol (Nimbus) will not relieve an asthma attack that has already started.

Fluticasone (Nimbus) and Salmeterol (Nimbus) is also used to treat air flow blockage and reduce the worsening of chronic obstructive pulmonary disease (COPD). This includes chronic bronchitis and emphysema.

Inhaled Fluticasone (Nimbus) belongs to the family of medicines known as corticosteroids or steroids (cortisone-like medicines). It works by preventing certain cells in the lungs and breathing passages from releasing substances that cause asthma symptoms.

Inhaled Salmeterol (Nimbus) is a long-acting bronchodilator. Bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. It relieves cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

Fluticasone (Nimbus) and Salmeterol (Nimbus) must be used with a short-acting medicine (e.g. albuterol) for an asthma attack or asthma symptoms that need attention right away.

Fluticasone (Nimbus) and Salmeterol (Nimbus) is available only with your doctor's prescription.

General

Nimbus should be administered as one inhalation twice daily by the orally inhaled route only. Advise the patient to rinse his/her mouth with water without swallowing after each dose.

Dosing

Nimbus should be administered as 1 inhalation twice daily (approximately 12 hours apart) by the orally inhaled route. Nimbus should be used at approximately the same time every day. Do not use Nimbus more than 2 times every 24 hours.

The starting dosage for Nimbus is based upon patients’ asthma severity. The usual recommended starting dose for patients not on inhaled corticosteroids is 55/14 mcg twice daily. For other patients, the starting dose should be based on previous asthma drug therapy and disease severity. For patients switching to Nimbus from another inhaled corticosteroid or combination product, select the low (55/14 mcg), medium (113/14 mcg) or high (232/14 mcg) dose strength of Nimbus based on the strength of the previous inhaled corticosteroid product or the strength of the inhaled corticosteroid from a combination product and disease severity. For patients who do not respond to Nimbus 55/14 mcg after 2 weeks of therapy, increasing the dose may provide additional asthma control.

If a dosage regimen of Nimbus fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g., replacing the current strength of Nimbus with a higher strength, or adding additional controller therapies) should be considered.

The highest recommended dose of Nimbus is 232/14 mcg twice daily. More frequent administration or a greater number of inhalations (more than one inhalation twice daily) of the prescribed strength of Nimbus is not recommended as some patients are more likely to experience adverse effects with higher doses of Salmeterol (Nimbus). Patients using Nimbus should not use additional LABA for any reason.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.

Improvement in asthma control following inhaled administration of Nimbus can occur within 15 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects.

For patients who do not respond adequately to the starting dose after 2 weeks of therapy, replacing the current strength of Nimbus with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Nimbus with a higher strength, adding additional controller therapies) should be considered.

Nimbus does not require priming. Do not use Nimbus with a spacer or volume holding chamber.

Cleaning:

Dose Counter: The Nimbus inhaler has a dose counter. When the patient receives the inhaler, the number 60 will be displayed. The dose counter will count down each time the mouthpiece is opened and closed. The dose counter window displays the number of actuations (inhalations) left in the inhaler in units of two (e.g., 60, 58, 56, etc.). When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red and the color of the numbers will change to black.

See also:
What is the most important information I should know about Nimbus?

Hypersensitivity to any of the excipients of Nimbus.

Nimbus is not for relief of acute symptoms for which a fast- and short-acting bronchodilator (eg, salbutamol) is required. Patients should be advised to have their relief medication available at all times.

Patients should not be initiated on Nimbus during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Use Nimbus as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Nimbus comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Nimbus refilled.
• Always activate and use this device in a level, horizontal position. Do NOT try to use a spacer device with Nimbus.
• Hold the device in one hand and put the thumb of your other hand on the thumb grip. Push your thumb away from you as far as it will go until the mouthpiece appears and snaps into position.
• Hold the device in a level, flat position with the mouthpiece toward you. Slide the lever away from you as far as it will go until it clicks.
• Do NOT close or tilt the device, play with the lever, or move the lever more than 1 time. This may release or waste extra doses.
• Hold the device away from your mouth and breathe out fully. Do NOT breathe into the inhaler. Put the mouthpiece to your lips. Breathe in quickly and deeply through the device.
• Remove the device from your mouth. Hold your breath for about 10 seconds, or as long as is comfortable. Then breathe out slowly.
• Close the device. Put your thumb on the thumb grip and slide it back toward you as far as it will go. The device will click shut and the lever will return to its original position.
• Your dose of medicine is a very fine powder. Most, but not all, patients can taste or feel the dose. Do NOT use another dose if you do not taste or feel the medicine. If you are not sure if you are receiving your dose, contact your doctor or pharmacist.
• Rinse your mouth with water after using Nimbus. DO NOT swallow the rinse solution. Spit the rinse water out.
• If you are using other inhaled medicines, wait a few minutes between using Nimbus and other inhalers, unless directed otherwise by your doctor.
• Take your doses of Nimbus about 12 hours apart unless your doctor tells you otherwise.
• Never wash the mouthpiece or any other part of the inhaler. Keep it dry. Store Nimbus in a dry place.
• Throw Nimbus away 1 month after you remove it from the foil pouch, or after the dose indicator reads "0," whichever comes first.
• You may breathe more easily after the first dose of Nimbus. However, it may take 1 week or longer to achieve the most benefit.
• Use Nimbus on a regular schedule to get the most benefit from it. Using Nimbus at the same times each day will help you remember to use it. Do not stop using Nimbus even if you feel better unless your doctor tells you to.
• If you miss a dose of Nimbus, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Nimbus.

This product is used to control and prevent symptoms (wheezing and shortness of breath) caused by asthma or ongoing lung disease (chronic obstructive pulmonary disease-COPD, which includes chronic bronchitis and emphysema). It contains 2 medications: Fluticasone (Nimbus) and Salmeterol (Nimbus). Fluticasone (Nimbus) belongs to a class of drugs known as corticosteroids. It works by reducing the irritation and swelling of the airways. Salmeterol (Nimbus) belongs to the class of drugs known as long-acting beta agonists. It works by opening airways in the lungs to make breathing easier. Controlling symptoms of breathing problems can decrease time lost from work or school.

This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden shortness of breath or asthma attacks. If sudden breathing problems occur, use your quick-relief inhaler (such as albuterol, also called salbutamol in some countries) as prescribed.

How to use Nimbus inhalation

Read the Medication Guide provided by your pharmacist before you start using this medication and each time you get a refill. Read the patient instructions for directions on how to use this inhaler properly. If you have any questions, ask your doctor or pharmacist.

Use this device in a level, flat position. Inhale this medication by mouth as directed by your doctor, usually twice daily (in the morning and evening, 12 hours apart). You may or may not taste/feel the drug when you inhale. Either is normal. Do not exhale into the device.

Do not take the inhaler apart or wash the mouthpiece or any part of the device. Close the device after each use.

If you are using other inhalers at the same time, wait at least 1 minute between the use of each medication, and use this drug last.

Gargle and rinse your mouth with water after each use of this medication to help prevent irritation and yeast infections (thrush) in the mouth and throat. Do not swallow the rinse water.

The dosage is based on your medical condition, age, and response to treatment.

Use this medication regularly in order to get the most benefit from it. This medication works best if used at evenly spaced intervals. To help you remember, use it at the same times each day. Do not increase your dose, use this medication more frequently, or stop using it without first consulting your doctor. Also, do not use other long-acting beta agonists while using this medication.

If you have been using a quick-relief inhaler (such as albuterol, also called salbutamol in some countries) on a regular daily schedule (such as 4 times daily), you must stop this schedule and only use the quick-relief inhaler as needed for sudden shortness of breath/asthma attacks. Consult your doctor for details.

If you are regularly using a different corticosteroid taken by mouth (such as prednisone), you should not stop using it unless directed by your doctor. You may have withdrawal symptoms if the drug is suddenly stopped. Some conditions (such as asthma, allergies) may become worse when the drug is suddenly stopped. To prevent withdrawal symptoms (such as weakness, weight loss, nausea, muscle pain, headache, tiredness, dizziness), your doctor may direct you to slowly lower the dose of your old medication after you begin using this product. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away. See also Precautions section.

It may take 1 week or longer before you get the full benefit of this drug. Tell your doctor if your condition does not improve or if it worsens.

Learn which of your inhalers you should use every day (controller drugs) and which you should use if your breathing suddenly worsens (quick-relief drugs). Ask your doctor ahead of time what you should do if you have new or worsening cough or shortness of breath, wheezing, increased sputum, worsening peak flow meter readings, waking up at night with trouble breathing, if you use your quick-relief inhaler more often (more than 2 days a week), or if your quick-relief inhaler does not seem to be working well. Learn when you can treat sudden breathing problems by yourself and when you must get medical help right away.

See also:
What other drugs will affect Nimbus?

Nimbus has been used concomitantly with other drugs, including short-acting beta-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of Salmeterol (Nimbus) and ketoconazole was associated with more frequent increases in QTc duration compared with Salmeterol (Nimbus) and placebo administration.

Monoamine Oxidase Inhibitors And Tricyclic Antidepressants

Nimbus should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of Salmeterol (Nimbus), a component of Nimbus, on the vascular system may be potentiated by these agents.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as Salmeterol (Nimbus), a component of Nimbus, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

Non–Potassium-Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non–potassiumsparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as Salmeterol (Nimbus), a component of Nimbus, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Nimbus with non–potassium-sparing diuretics.

See also:
What are the possible side effects of Nimbus?

LABA, such as Salmeterol (Nimbus), one of the active ingredients in Nimbus, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of Salmeterol (Nimbus) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving Salmeterol (Nimbus). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Pneumonia in patients with COPD
• Immunosuppression
• Hypercorticism and adrenal suppression
• Reduction in bone mineral density
• Growth effects
• Glaucoma and cataracts

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

Clinical Trials Experience In Asthma

Adult And Adolescent Subjects Aged 12 Years And Older

The incidence of adverse reactions associated with Nimbus in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (349 females and 356 males) previously treated with Salmeterol (Nimbus) or inhaled corticosteroids were treated twice daily with Nimbus (100/50-or 250/50-mcg doses), Fluticasone (Nimbus) propionate inhalation powder (100-or 250-mcg doses), Salmeterol (Nimbus) inhalation powder 50 mcg, or placebo. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group.

Table 2: Adverse Reactions with Nimbus with ≥ 3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma

The types of adverse reactions and events reported in Trial 3, a 28-week non-U.S. clinical trial in 503 subjects previously treated with inhaled corticosteroids who were treated twice daily with Nimbus 500/50, Fluticasone (Nimbus) propionate inhalation powder 500 mcg and Salmeterol (Nimbus) inhalation powder 50 mcg used concurrently, or Fluticasone (Nimbus) propionate inhalation powder 500 mcg, were similar to those reported in Table 2.

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with Nimbus compared with subjects treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum.

Pediatric Subjects Aged 4 To 11 Years

The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks' treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving inhaled corticosteroids at trial entry were randomized to either Nimbus 100/50 or Fluticasone (Nimbus) propionate inhalation powder 100 mcg twice daily. Common adverse reactions (greater than or equal to 3% and greater than placebo) seen in the pediatric subjects but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections.

Laboratory Test Abnormalities

Elevation of hepatic enzymes was reported in greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

Short-Term (6 Months to 1 Year) Trials

The short-term safety data are based on exposure to Nimbus 250/50 twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, a total of 723 adult subjects (266 females and 457 males) were treated twice daily with Nimbus 250/50, Fluticasone (Nimbus) propionate inhalation powder 250 mcg, Salmeterol (Nimbus) inhalation powder, or placebo. The mean age of the subjects was 64, and the majority (93%) was Caucasian. In this trial, 70% of the subjects treated with Nimbus reported an adverse reaction compared with 64% on placebo. The average duration of exposure to Nimbus 250/50 was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month trial is shown in Table 3.

Table 3: Overall Adverse Reactions with Nimbus 250/50 with ≥ 3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis

In the two 1-year trials, Nimbus 250/50 was compared with Salmeterol (Nimbus) in 1,579 subjects (863 males and 716 females). The mean age of the subjects was 65 years, and the majority (94%) was Caucasian. To be enrolled, all of the subjects had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the subjects treated with Nimbus and 86% of the subjects treated with Salmeterol (Nimbus) reported an adverse event. The most common events that occurred with a frequency of greater than 5% and more frequently in the subjects treated with Nimbus were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia. Overall, 55 (7%) of the subjects treated with Nimbus and 25 (3%) of the subjects treated with Salmeterol (Nimbus) developed pneumonia.

The incidence of pneumonia was higher in subjects older than 65 years, 9% in the subjects treated with Nimbus compared with 4% in the subjects treated with Nimbus younger than 65 years. In the subjects treated with Salmeterol (Nimbus), the incidence of pneumonia was the same (3%) in both age-groups.

Long-Term (3 Years) Trial

The safety of Nimbus 500/50 was evaluated in a randomized, double-blind, placebo-controlled, multicenter, international, 3-year trial in 6,184 adult subjects with COPD (4,684 males and 1,500 females). The mean age of the subjects was 65 years, and the majority (82%) was Caucasian. The distribution of adverse events was similar to that seen in the 1-year trials with Nimbus 250/50. In addition, pneumonia was reported in a significantly increased number of subjects treated with Nimbus 500/50 and Fluticasone (Nimbus) propionate 500 mcg (16% and 14%, respectively) compared with subjects treated with Salmeterol (Nimbus) 50 mcg or placebo (11% and 9%, respectively). When adjusted for time on treatment, the rates of pneumonia were 84 and 88 events per 1,000 treatment-years in the groups treated with Fluticasone (Nimbus) propionate 500 mcg and with Nimbus 500/50, respectively, compared with 52 events per 1,000 treatment-years in the Salmeterol (Nimbus) and placebo groups. Similar to what was seen in the 1-year trials with Nimbus 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with Nimbus 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with Nimbus 500/50 versus 8% with placebo).

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with COPD treated with Nimbus compared with subjects treated with placebo include the following: syncope; ear, nose, and throat infections; ear signs and symptoms; laryngitis; nasal congestion/blockage; nasal sinus disorders; pharyngitis/throat infection; hypothyroidism; dry eyes; eye infections; gastrointestinal signs and symptoms; oral lesions; abnormal liver function tests; bacterial infections; edema and swelling; viral infections.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no increased reporting of neutrophilia or changes in glucose or potassium was noted.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of Nimbus, Fluticasone (Nimbus) propionate, and/or Salmeterol (Nimbus) regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Nimbus, Fluticasone (Nimbus) propionate, and/or Salmeterol (Nimbus) or a combination of these factors.

Cardiac Disorders

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders

Cushing's syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders

Glaucoma.

Gastrointestinal Disorders

Abdominal pain, dyspepsia, xerostomia.

Immune System Disorders

Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.

Infections And Infestations

Esophageal candidiasis.

Metabolic and Nutrition Disorders

Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, And Bone Disorders

Arthralgia, cramps, myositis, osteoporosis. Nervous System Disorders Paresthesia, restlessness.

Psychiatric Disorders

Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Reproductive System And Breast Disorders

Dysmenorrhea.

Respiratory, Thoracic, And Mediastinal Disorders

Chest congestion; chest tightness; dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin And Subcutaneous Tissue Disorders

Ecchymoses, photodermatitis.

Vascular Disorders

Pallor.