PROVENTIL HFA Inhalation aerosol Ref.[10614] Active ingredients: Salbutamol

1. Paradoxical Bronchospasm: Inhaled albuterol sulfate can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROVENTIL HFA Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.
2. Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of PROVENTIL HFA Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
3. Use of Anti-inflammatory Agents: The use of beta-adrenergic-agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.
4. Cardiovascular Effects: PROVENTIL HFA Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROVENTIL HFA Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, PROVENTIL HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
5. Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
6. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

Adverse reaction information concerning PROVENTIL HFA Inhalation Aerosol is derived from a 12-week, double-blind, double-dummy study which compared PROVENTIL HFA Inhalation Aerosol, a CFC 11/12 propelled albuterol inhaler, and an HFA-134a placebo inhaler in 565 asthmatic patients. The following table lists the incidence of all adverse events (whether considered by the investigator drug related or unrelated to drug) from this study which occurred at a rate of 3% or greater in the PROVENTIL HFA Inhalation Aerosol treatment group and more frequently in the PROVENTIL HFA Inhalation Aerosol treatment group than in the placebo group. Overall, the incidence and nature of the adverse reactions reported for PROVENTIL HFA Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler were comparable.

Adverse Experience Incidences (% of patients) in a Large 12-week Clinical Trial:

^* This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of at least 3.0% in the PROVENTIL HFA Inhalation Aerosol group and more frequently in the PROVENTIL HFA Inhalation Aerosol group than in the HFA-134a placebo inhaler group.

Adverse events reported by less than 3% of the patients receiving PROVENTIL HFA Inhalation Aerosol, and by a greater proportion of PROVENTIL HFA Inhalation Aerosol patients than placebo patients, which have the potential to be related to PROVENTIL HFA Inhalation Aerosol include: dysphonia, increased sweating, dry mouth, chest pain, edema, rigors, ataxia, leg cramps, hyperkinesia, eructation, flatulence, tinnitus, diabetes mellitus, anxiety, depression, somnolence, rash. Palpitation and dizziness have also been observed with PROVENTIL HFA Inhalation Aerosol.

Adverse events reported in a 4-week pediatric clinical trial comparing PROVENTIL HFA Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler occurred at a low incidence rate and were similar to those seen in the adult trials.

In small, cumulative dose studies, tremor, nervousness, and headache appeared to be dose related.

Rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema have been reported after the use of inhaled albuterol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, insomnia, headache, metabolic acidosis, and drying or irritation of the oropharynx.

Albuterol sulfate, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

See illustrated Patient’s Instructions for Use. SHAKE WELL BEFORE USING. Patients should be given the following information:

It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four “test sprays” into the air, away from the face.

KEEPING THE PLASTIC MOUTHPIECE CLEAN IS VERY IMPORTANT TO PREVENT MEDICATION BUILDUP AND BLOCKAGE. THE MOUTHPIECE SHOULD BE WASHED, SHAKEN TO REMOVE EXCESS WATER, AND AIR DRIED THOROUGHLY AT LEAST ONCE A WEEK. INHALER MAY CEASE TO DELIVER MEDICATION IF NOT PROPERLY CLEANED.

The mouthpiece should be cleaned (with the canister removed) by running warm water through the top and bottom for 30 seconds at least once a week. The mouthpiece must be shaken to remove excess water, then air dried thoroughly (such as overnight). Blockage from medication buildup or improper medication delivery may result from failure to thoroughly air dry the mouthpiece.

If the mouthpiece should become blocked (little or no medication coming out of the mouthpiece), the blockage may be removed by washing as described above.

If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, test spray twice away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly.

The action of PROVENTIL HFA Inhalation Aerosol should last up to 4 to 6 hours. PROVENTIL HFA Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses of PROVENTIL HFA Inhalation Aerosol without consulting your physician. If you find that treatment with PROVENTIL HFA Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking PROVENTIL HFA Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by your physician.

Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. If you are pregnant or nursing, contact your physician about use of PROVENTIL HFA Inhalation Aerosol. Effective and safe use of PROVENTIL HFA Inhalation Aerosol includes an understanding of the way that it should be administered. Use PROVENTIL HFA Inhalation Aerosol only with the actuator supplied with the product. Discard the canister after 200 sprays have been used.

In general, the technique for administering PROVENTIL HFA Inhalation Aerosol to children is similar to that for adults. Children should use PROVENTIL HFA Inhalation Aerosol under adult supervision, as instructed by the patient’s physician. (See Patient’s Instructions for Use.)

1. Beta-Blockers: Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROVENTIL HFA Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.
2. Diuretics: The ECG changes and/or hypokalemia which may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, 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 beta-agonists with nonpotassium-sparing diuretics.
3. Albuterol-Digoxin: Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear; nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol.
4. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: PROVENTIL HFA Inhalation Aerosol 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 albuterol on the cardiovascular system may be potentiated.

Teratogenic Effects

Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at 50 mg/kg dose (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

In an inhalation reproduction study in SPRAGUE-DAWLEY rats, the albuterol sulfate/HFA-134a formulation did not exhibit any teratogenic effects at 10.5 mg/kg (approximately 70 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

There are no adequate and well-controlled studies of PROVENTIL HFA Inhalation Aerosol or albuterol sulfate in pregnant women. PROVENTIL HFA Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Because of the potential for beta-agonist interference with uterine contractility, use of PROVENTIL HFA Inhalation Aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis

Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta₂-agonists, including albuterol.

Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROVENTIL HFA Inhalation Aerosol are excreted in human milk.

Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROVENTIL HFA Inhalation Aerosol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when albuterol sulfate is administered to a nursing woman.

The safety and effectiveness of PROVENTIL HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established.

PROVENTIL HFA Inhalation Aerosol has not been studied in a geriatric population. As with other beta₂-agonists, special caution should be observed when using PROVENTIL HFA Inhalation Aerosol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.