Ventolin

Generic Name: albuterol sulfate

Dosage Form: aerosol, metered
FULL PRESCRIBING INFORMATION

Indications and Usage for Ventolin

Bronchospasm

Ventolin HFA is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease.

Exercise-Induced Bronchospasm

Ventolin HFA is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

Ventolin Dosage and Administration

Administer Ventolin HFA by oral inhalation only. Shake Ventolin HFA well before each spray.

Bronchospasm

For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the usual dosage for adults and children is 2 inhalations repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not recommended.

Exercise-Induced Bronchospasm

The usual dosage for adults and children 4 years of age and older is 2 inhalations 15 to 30 minutes before exercise.

Administration Information

Priming: Priming Ventolin HFA is essential to ensure appropriate albuterol content in each actuation. Prime Ventolin HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime Ventolin HFA, release 4 sprays into the air away from the face, shaking well before each spray.

Cleaning: To ensure proper dosing and to prevent actuator orifice blockage, wash the actuator with warm water and let it air-dry completely at least once a week.

Dose Counter: Ventolin HFA has a dose counter attached to the canister that starts at 204 or 64 and counts down each time a spray is released [see Dosage Forms and Strengths (3)]. When the counter reads 020, the patient should contact the pharmacist for a refill of medication or consult the physician to determine whether a prescription refill is needed.

Ventolin HFA comes in a moisture-protective foil pouch, which should be removed prior to use. Discard Ventolin HFA when the counter reads 000 or 12 months after removal from the moisture-protective foil pouch, whichever comes first [see Dosage Forms and Strengths (3)].

See 17.8 FDA-Approved Patient Labeling for instructions on how to prime and clean the inhaler to ensure proper dosing and to prevent actuator orifice blockage.

Dosage Forms and Strengths

Ventolin HFA is an inhalation aerosol. Each actuation contains 108 mcg albuterol sulfate (90 mcg albuterol base) from the mouthpiece. Ventolin HFA is supplied as an 18-g pressurized aluminum canister with dose counter fitted with a blue plastic actuator and a blue strapcap; this canister contains 200 actuations. Ventolin HFA is also supplied as an 8-g pressurized aluminum canister with dose counter fitted with a blue plastic actuator and a blue strapcap; this canister contains 60 actuations.

Contraindications

Ventolin HFA is contraindicated in patients with a history of hypersensitivity to albuterol or any other components of Ventolin HFA. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate.

Warnings and Precautions

Paradoxical Bronchospasm

Inhaled albuterol sulfate can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Ventolin HFA 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.

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 Ventolin HFA than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

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.

Cardiovascular Effects

Ventolin HFA, like all other beta2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, Ventolin HFA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical relevance of these findings is unknown. Therefore, Ventolin HFA, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

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.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of albuterol sulfate inhalation aerosol, as demonstrated by cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Discontinue Ventolin HFA if immediate hypersensitivity reactions occur.

Coexisting Conditions

Ventolin HFA, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia

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.

Adverse Reactions

Use of Ventolin HFA may be associated with the following:

• Paradoxical bronchospasm [see Warnings and Precautions (5.1)]


• Cardiovascular effects [see Warnings and Precautions (5.4)]


• Immediate hypersensitivity reactions [see Warnings and Precautions (5.6)]


• Hypokalemia [see Warnings and Precautions (5.8)]

Clinical Trials Experience

The safety data described below reflects exposure to Ventolin HFA in 248 patients treated with Ventolin HFA in 3 placebo-controlled clinical trials of 2 to 12 weeks’ duration. The data from adults and adolescents is based upon 2 clinical trials in which 202 patients with asthma 12 years of age and older were treated with Ventolin HFA 2 inhalations 4 times daily for 12 weeks’ duration. The adult/adolescent population was 92 female, 110 male and 163 white, 19 black, 18 Hispanic, 2 other. The data from pediatric patients are based upon 1 clinical trial in which 46 patients with asthma 4 to 11 years of age were treated with Ventolin HFA 2 inhalations 4 times daily for 2 weeks’ duration. The population was 21 female, 25 male and 25 white, 17 black, 3 Hispanic, 1 other.

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

Adults and Adolescents 12 Years of Age and Older:The two 12-week, randomized, double-blind studies in 610 adolescent and adult patients with asthma that compared Ventolin HFA, a CFC 11/12-propelled albuterol inhaler, and an HFA-134a placebo inhaler. Overall, the incidence and nature of the adverse reactions reported for Ventolin HFA and a CFC 11/12-propelled albuterol inhaler were comparable. Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these studies that occurred at a rate of 3% or greater in the group treated with Ventolin HFA and more frequently in the group treated with Ventolin HFA than in the HFA-134a placebo inhaler group.

Table 1. Overall Adverse Reactions With ≥3% Incidence in 2 Large 12-Week Clinical Trials in Adolescents and Adults*

Adverse Reaction	Percent of Patients
	Ventolin HFA (n = 202) %	CFC 11/12-Propelled Albuterol Inhaler (n = 207) %	Placebo HFA-134a (n = 201) %
Ear, nose, and throat
Throat irritation	10	6	7
Upper respiratory inflammation	5	5	2
Lower respiratory
Viral respiratory infections	7	4	4
Cough	5	2	2
Musculoskeletal
Musculoskeletal pain	5	5	4
*This table includes all adverse reactions (whether considered by the investigator to be drug-related or unrelated to drug) that occurred at an incidence rate of at least 3.0% in the group treated with Ventolin HFA and more frequently in the group treated with Ventolin HFA than in the HFA-134a placebo inhaler group.

Adverse reactions reported by less than 3% of the adolescent and adult patients receiving Ventolin HFA and by a greater proportion of patients receiving Ventolin HFA than receiving HFA-134a placebo inhaler and that have the potential to be related to Ventolin HFA include diarrhea, laryngitis, oropharyngeal edema, cough, lung disorders, tachycardia, and extrasystoles. Palpitation and dizziness have also been observed with Ventolin HFA.

Pediatric Patients: Results from the 2-week pediatric clinical study in patients with asthma 4 to 11 years of age showed that this pediatric population had an adverse reaction profile similar to that of the adolescent and adult populations.

Three studies have been conducted to evaluate the safety and efficacy of Ventolin HFA in patients between birth and 4 years of age. The results of these studies did not establish the efficacy of Ventolin HFA in this age-group [see Pediatric Use (8.4)]. Since the efficacy of Ventolin HFA has not been demonstrated in children between birth and 48 months of age, the safety of Ventolin HFA in this age-group cannot be established. However, the safety profile observed in the pediatric population under 4 years of age was comparable to that observed in the older pediatric patients and in adolescents and adults. Where adverse reaction incidence rates were greater in patients under 4 years of age compared with older patients, the higher incidence rates were noted in all treatment arms, including placebo. These adverse reactions included upper respiratory tract infection, nasopharyngitis, pyrexia, and tachycardia.

Postmarketing Experience

In addition to the adverse reactions listed in section 6.1, the following adverse reactions have been identified during postapproval use of Ventolin HFA. 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.

Cases of paradoxical bronchospasm, hoarseness, arrhythmias (including atrial fibrillation, supraventricular tachycardia), and hypersensitivity reactions (including urticaria, angioedema, rash) have been reported after the use of Ventolin HFA.

In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypokalemia, hypertension, peripheral vasodilatation, angina, tremor, central nervous system stimulation, hyperactivity, sleeplessness, headache, muscle cramps, and drying or irritation of the oropharynx.

Drug Interactions

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Beta-Blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Ventolin HFA, but may produce severe bronchospasm in patients with asthma. 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.

Diuretics

The ECG changes and/or hypokalemia that 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 relevance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. Consider monitoring potassium levels.

Digoxin

Mean decreases of 16% to 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 relevance of these findings for patients with obstructive airway disease who are receiving inhaled 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.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

Ventolin HFA 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 vascular system may be potentiated. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies of Ventolin HFA or albuterol sulfate in pregnant women. 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. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. Ventolin HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at exposures approximately equal to the maximum recommended human dose (MRHD) for adults on a mg/m2 basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHD. Similar effects were not observed at approximately one eleventh of the MRHD. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

In a rabbit reproduction study, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 680 times the MRHD.

In another rabbit study, an albuterol sulfate/HFA-134a formulation administered by inhalation produced enlargement of the frontal portion of the fetal fontanelles at approximately one third of the MRHD [see Animal Toxicology and/or Pharmacology (13.2)].

Labor and Delivery

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

Nursing Mothers

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 Ventolin HFA 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 Ventolin HFA 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 Ventolin HFA is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Ventolin HFA in children 4 years of age and older has been established based upon two 12-week clinical trials in patients 12 years of age and older with asthma and one 2-week clinical trial in patients 4 to 11 years of age with asthma [see Clinical Studies (14.1), Adverse Reactions (6.1)]. The safety and effectiveness of Ventolin HFA in children under 4 years of age has not been established. Three studies have been conducted to evaluate the safety and efficacy of Ventolin HFA in patients under 4 years of age and the findings are described below.

Two 4-week randomized, double-blind, placebo-controlled studies were conducted in 163 pediatric patients from birth to 48 months of age with symptoms of bronchospasm associated with obstructive airway disease (presenting symptoms included: wheeze, cough, dyspnea, or chest tightness). Ventolin HFA or placebo HFA was delivered with either an AeroChamber Plus® Valved Holding Chamber or an Optichamber® Valved Holding Chamber with mask 3 times daily. In one study, Ventolin HFA 90 mcg (N = 26), Ventolin HFA 180 mcg (N = 25), and placebo HFA (N = 26) were administered to children between 24 and 48 months of age. In the second study, Ventolin HFA 90 mcg (N = 29), Ventolin HFA 180 mcg (N = 29), and placebo HFA (N = 28) were administered to children between birth and 24 months of age. Over the 4-week treatment period, there were no treatment differences in asthma symptom scores between the groups receiving Ventolin HFA 90 mcg, Ventolin HFA 180 mcg, and placebo in either study.

In a third study, Ventolin HFA was evaluated in 87 pediatric patients younger than 24 months of age for the treatment of acute wheezing. Ventolin HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this study. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between Ventolin HFA 180 mcg and Ventolin HFA 360 mcg.

In vitro dose characterization studies were performed to evaluate the delivery of Ventolin HFA via holding chambers with facemasks. The studies were conducted with 2 different holding chambers with facemasks (small and medium size). The in vitro study data when simulated to patients suggest that the dose of Ventolin HFA presented for inhalation via a valved holding chamber with facemask will be comparable to the dose delivered in adults without a spacer and facemask per kilogram of body weight (Table 2). However, clinical studies in children under 4 years of age described above suggest that either the optimal dose of Ventolin HFA has not been defined in this age-group or Ventolin HFA is not effective in this age-group. The safety and effectiveness of Ventolin HFA administered with or without a spacer device in children under 4 years of age has not been demonstrated.

Table 2: In Vitro Medication Delivery Through AeroChamber Plus® Valved Holding Chamber With a Facemask

Age	Facemask	Flow Rate (L/min)	Holding Time (seconds)	Mean Medication Delivery Through AeroChamber Plus (mcg/actuation)	Body Weight 50th Percentile (kg)*	Medication Delivered per Actuation (mcg/kg)†
6 to 12 Months	Small	4.9	0 2 5 10	18.2 19.8 13.8 15.4	7.5-9.9	1.8-2.4 2.0-2.6 1.4-1.8 1.6-2.1
2 to 5 Years	Small	8.0	0 2 5 10	17.8 16.0 16.3 18.3	12.3-18.0	1.0-1.4 0.9-1.3 0.9-1.3 1.0-1.5
2 to 5 Years	Medium	8.0	0 2 5 10	21.1 15.3 18.3 18.2	12.3-18.0	1.2-1.7 0.8-1.2 1.0-1.5 1.0-1.5
>5 Years	Medium	12.0	0 2 5 10	26.8 20.9 19.6 20.3	18.0	1.5 1.2 1.1 1.1
*Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated. †A single inhalation of Ventolin HFA in a 70-kg adult without use of a valved holding chamber and facemask delivers approximately 90 mcg, or 1.3 mcg/kg.

Geriatric Use

Clinical studies of Ventolin HFA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, sleeplessness. Hypokalemia may also occur.

As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of Ventolin HFA. Treatment consists of discontinuation of Ventolin HFA together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Ventolin HFA.

The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals.

Ventolin Description

The active component of Ventolin HFA is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name α1-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α′-diol sulfate (2:1)(salt) and the following chemical structure:

Albuterol sulfate is a white crystalline powder with a molecular weight of 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. It is soluble in water and slightly soluble in ethanol.

The World Health Organization recommended name for albuterol base is salbutamol.

Ventolin HFA is a pressurized metered-dose aerosol unit fitted with a counter. Ventolin HFA is intended for oral inhalation only. Each unit contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients.

Priming Ventolin HFA is essential to ensure appropriate albuterol content in each actuation. To prime the inhaler, release 4 sprays into the air away from the face, shaking well before each spray. The inhaler should be primed before using it for the first time, when it has not been used for more than 2 weeks, or when it has been dropped.

After priming, each actuation of the inhaler delivers 120 mcg of albuterol sulfate, USP in 75 mg of suspension from the valve and 108 mcg of albuterol sulfate, USP from the mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece).

Each 18-g canister provides 200 inhalations. Each 8-g canister provides 60 inhalations.

This product does not contain chlorofluorocarbons (CFCs) as the propellant.

Ventolin - Clinical Pharmacology

Mechanism of Action

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions (5.4)].

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes [see Warnings and Precautions (5.4)].

Pharmacokinetics

The systemic levels of albuterol are low after inhalation of recommended doses. A study conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when albuterol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of Ventolin HFA (Tmax = 0.42 hours) as compared to CFC-propelled albuterol inhaler (Tmax = 0.17 hours). Apparent terminal plasma half-life of albuterol is approximately 4.6 hours. No further pharmacokinetic studies for Ventolin HFA were conducted in neonates, children, or elderly subjects.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2.0 mg/kg (approximately 14 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 6 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1,700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 225 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 340 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

Animal Toxicology and/or Pharmacology

Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (380 to 1,300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

Reproductive Toxicology Studies: 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 fetuses (37%) when albuterol sulfate was administered orally at a 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 New Zealand white rabbits, albuterol sulfate/HFA-134a formulation exhibited enlargement of the frontal portion of the fetal fontanelles at and above inhalation doses of 0.0193 mg/kg (less than 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.

Clinical Studies

Bronchospasm Associated With Asthma

Adult and Adolescent Patients 12 Years of Age and Older: The efficacy of Ventolin HFA was evaluated in two 12-week, randomized, double-blind, placebo controlled trials in patients 12 years of age and older with mild to moderate asthma. These trials included a total of 610 patients (323 males, 287 females). In each trial, patients received 2 inhalations of Ventolin HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo 4 times daily for 12 weeks’ duration. Patients taking the HFA-134a placebo inhaler also took Ventolin HFA for asthma symptom relief on an as-needed basis. Some patients who participated in these clinical trials were using concomitant inhaled steroid therapy. Efficacy was assessed by serial forced expiratory volume in 1 second (FEV1). In each of these trials, 2 inhalations of Ventolin HFA produced significantly greater improvement in FEV1 over the pretreatment value than placebo. Results from the 2 clinical trials are described below.

In a 12-week, randomized, double-blind study, Ventolin HFA (101 patients) was compared to CFC 11/12-propelled albuterol (99 patients) and an HFA-134a placebo inhaler (97 patients) in adolescent and adult patients 12 to 76 years of age with mild to moderate asthma. Serial FEV1 measurements [shown below as percent change from test-day baseline at Day 1 (n = 297) and at Week 12 (n = 249)] demonstrated that 2 inhalations of Ventolin HFA produced significantly greater improvement in FEV1 over the pretreatment value than placebo.

FEV1 as Percent Change From Predose in a Large, 12-Week Clinical Trial

Day 1

Week 12

In the responder population (≥15% increase in FEV1 within 30 minutes postdose) treated with Ventolin HFA, the mean time to onset of a 15% increase in FEV1 over the pretreatment value was 5.4 minutes, and the mean time to peak effect was 56 minutes. The mean duration of effect as measured by a 15% increase in FEV1 over the pretreatment value was approximately 4 hours. In some patients, duration of effect was as long as 6 hours.

The second 12-week randomized, double-blind study was conducted to evaluate the efficacy and safety of switching patients from CFC 11/12-propelled albuterol to Ventolin HFA. During the 3-week run-in phase of the study, all patients received CFC 11/12-propelled albuterol. During the double-blind treatment phase, Ventolin HFA (91 patients) was compared to CFC 11/12-propelled albuterol (100 patients) and an HFA-134a placebo inhaler (95 patients) in adolescent and adult patients with mild to moderate asthma. Serial FEV1 measurements demonstrated that 2 inhalations of Ventolin HFA produced significantly greater improvement in pulmonary function than placebo. The switching from CFC 11/12-propelled albuterol inhaler to Ventolin HFA did not reveal any clinically significant changes in the efficacy profile.

In the 2 adult studies, the efficacy results from Ventolin HFA were significantly greater than placebo and were clinically comparable to those achieved with CFC 11/12-propelled albuterol, although small numerical differences in mean FEV1 response and other measures were observed. Physicians should recognize that individual responses to beta-adrenergic agonists administered via different propellants may vary and that equivalent responses in individual patients should not be assumed.

Pediatric Patients 4 Years of Age: The efficacy of Ventolin HFA was evaluated in one 2-week, randomized, double-blind, placebo-controlled trial in 135 pediatric patients 4 to 11 years of age with mild to moderate asthma. In this trial, patients received Ventolin HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo. Serial pulmonary function measurements demonstrated that 2 inhalations of Ventolin HFA produced significantly greater improvement in pulmonary function than placebo and that there were no significant differences between the groups treated with Ventolin HFA and CFC 11/12-propelled albuterol. In the responder population treated with Ventolin HFA, the mean time to onset of a 15% increase in peak expiratory flow rate (PEFR) over the pretreatment value was 7.8 minutes, and the mean time to peak effect was approximately 90 minutes. The mean duration of effect as measured by a 15% increase in PEFR over the pretreatment value was greater than 3 hours. In some patients, duration of effect was as long as 6 hours.

Exercise-Induced Bronchospasm

One controlled clinical study in adult patients with asthma (N = 24) demonstrated that 2 inhalations of Ventolin HFA taken approximately 30 minutes prior to exercise significantly prevented exercise-induced bronchospasm (as measured by maximum percentage fall in FEV1 following exercise) compared to an HFA-134a placebo inhaler. In addition, Ventolin HFA was shown to be clinically comparable to a CFC 11/12-propelled albuterol inhaler for this indication.

How Supplied/Storage and Handling

Ventolin HFA (albuterol sulfate) Inhalation Aerosol is supplied in the following packs as a pressurized aluminum canister fitted with a counter with a blue plastic actuator and a blue strapcap packaged within a moisture-protective foil pouch that also contains a desiccant:

NDC 0173-0682-20 18-g canister containing 200 actuations

NDC 0173-0682-21 8-g canister containing 60 actuations

NDC 0173-0682-24 8-g institutional pack canister containing 60 actuations

Before using, Ventolin HFA should be removed from the moisture-protective foil pouch. The pouch and dessicant should be discarded. Ventolin HFA should be discarded 12 months after removal from the pouch.

Priming Ventolin HFA is essential to ensure appropriate albuterol content in each actuation. To prime the inhaler, release 4 sprays into the air away from the face, shaking well before each spray. The inhaler should be primed before using it for the first time, when the inhaler has not been used for more than 2 weeks, or when it has been dropped.

After priming, each actuation delivers 120 mcg of albuterol sulfate, USP in 75 mg of suspension from the valve and 108 mcg of albuterol sulfate, USP from the mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece).

To ensure proper dosing and to prevent actuator orifice blockage, wash the actuator with warm water and let it air-dry completely at least once a week [see FDA-Approved Patient Labeling (17.8)].

The blue actuator supplied with Ventolin HFA should not be used with any other product canisters, and actuators from other products should not be used with a Ventolin HFA canister.

Ventolin HFA has a counter attached to the canister. The counter starts at 204 or 64 and counts down each time a spray is released. The correct amount of medication in each inhalation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. Ventolin HFA should be

phenylephrine nasal

Generic Name: phenylephrine nasal (FEN il EFF rin)

Brand names: 4-Way, 4-Way Menthol, Afrin 4 Hour Extra Moisturizing, Little Noses Decongestant, Neo-Synephrine Extra Strength Nasal, Neo-Synephrine Mild Nasal, Neo-Synephrine Nasal, Sinex Nasal Spray, Sinex Ultra Fine Mist, Alconefrin-12, Nostril Nasal Decongestant, Rhinall, Nasal Four

What is phenylephrine nasal?

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

Phenylephrine nasal is used to treat nasal congestion and sinus pressure caused by allergies, the common cold, or the flu. Phenylephrine may be used to treat congestion of the tubes that drain fluid from your inner ears, called the eustachian (yoo-STAY-shun) tubes.

Phenylephrine nasal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about phenylephrine nasal?

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

You should not use this medication if you are allergic to phenylephrine.

Do not use phenylephrine nasal if you have used linezolid (Zyvox) or procarbazine (Matulane), or if you have taken a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life-threatening side effects can occur if you use phenylephrine before these other drugs have cleared from your body.

Before using phenylephrine nasal, tell your doctor if you are allergic to any decongestants, or if you have heart disease, heart rhythm disorder, high blood pressure, diabetes, glaucoma, a thyroid disorder, or an enlarged prostate or urination problems.

Phenylephrine may interact with heart or blood pressure medications, antidepressants, diabetes medications, and other decongestants.

Never use more of this medicine than directed on the label or prescribed by your doctor.

Call your doctor if your symptoms do not improve after 3 days of using phenylephrine nasal, or if they get worse and you also have a fever. Using phenylephrine nasal too long can damage the lining of your nasal passages and lead to chronic nasal congestion.

What should I discuss with my healthcare provider before using phenylephrine nasal?

You should not use this medication if you are allergic to phenylephrine.

Do not use phenylephrine nasal if you have used linezolid (Zyvox) or procarbazine (Matulane), or if you have taken a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life-threatening side effects can occur if you use phenylephrine before these other drugs have cleared from your body.

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

• 
  

  heart disease, heart rhythm disorder;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  a thyroid disorder; or

  
  


• 
  

  an enlarged prostate or urination problems.

  
  

FDA pregnancy category C. Is not known whether this medication will harm an unborn baby. Before using phenylephrine nasal, tell doctor if you are pregnant. Phenylephrine nasal may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Older adults may be more likely to have side effects from this medication.

How should I use phenylephrine nasal?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cold medicine should be used only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Phenylephrine nasal is usually used every 4 hours. Follow the directions on the medicine label. Never use more of this medicine than directed on the label or prescribed by your doctor. Using phenylephrine nasal too long can damage the lining of your nasal passages and lead to chronic nasal congestion.

Gently blow your nose to clear any mucus before using this medication.

To use the nasal spray, insert the tip of the spray bottle into your nostril, past the middle of the inside of your nose (the nasal septum). Gently press your other nostril closed with your finger.

Keep your head upright, and squeeze the bottle while breathing in deeply through your nose. Sniff quickly a few times to get the medicine deep into your nasal passages.

Repeat these steps to use the medicine in your other nostril if needed.

After each use, clean the tip of the spray bottle with a clean tissue or rinse it with hot water, making sure that no water gets into the medicine bottle. Keep the cap on the bottle when not in use.

To use the nasal drops, lie on your back with your head tilted back. Insert the correct number of drops and remain lying in this position for several minutes. Gently turn your head from side to side.

Call your doctor if your symptoms do not improve after 3 days of using phenylephrine nasal, or if they get worse and you also have a fever.

If you need to have any type of surgery, tell the surgeon ahead of time if you have used phenylephrine nasal within the past few days.

Store at room temperature away from moisture and heat. To prevent the spread of infection, do not share this medication with anyone else.

What happens if I miss a dose?

Since phenylephrine nasal is usually used only when needed, you may not be on a dosing schedule. If you are using the medication regularly, use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe dizziness or drowsiness, slow heart rate, and fainting.

What should I avoid while using phenylephrine nasal?

Avoid getting this medication in your eyes. Ask a doctor or pharmacist before using any other cold, cough, or allergy medicine. Phenylephrine is contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains phenylephrine.

Phenylephrine nasal side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using phenylephrine and call your doctor at once if you have a serious side effect such as:

• 
  

  severe sneezing, runny or stuffy nose, redness or swelling in your nose, or other worsening nasal symptoms (may be a sign of overuse of phenylephrine nasal);

  
  


• 
  

  severe stinging, burning, or irritation inside your nose;

  
  


• 
  

  severe dizziness, restless feeling, nervousness, or insomnia;

  
  


• 
  

  mood changes, unusual thoughts or behavior;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  slow, fast, or pounding heartbeat;

  
  


• 
  

  tremors or shaking; or

  
  


• 
  

  urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  temporary sneezing;

  
  


• 
  

  mild burning, dryness, cold feeling, or irritation inside your nose;

  
  


• 
  

  headache, dizziness, weakness;

  
  


• 
  

  sweating, nausea;

  
  


• 
  

  feeling excited or restless (especially in children); or

  
  


• 
  

  mild sleep problems.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Phenylephrine nasal Dosing Information

Usual Adult Dose for Nasal Congestion:

Phenylephrine nasal 1% spray: 2 to 3 sprays in each nostril every 4 hours.

Usual Pediatric Dose for Nasal Congestion:

Phenylephrine nasal 0.125% drops:
2 to 6 years: Instill 2 to 3 drops in each nostril not more than every 4 hours under adult supervision.

Phenylephrine nasal 1% spray:
6 years or older: 2 to 3 sprays in each nostril every 4 hours.

What other drugs will affect phenylephrine nasal?

Tell your doctor about all other medications you use, especially:

• 
  

  other decongestants;

  
  


• 
  

  medicine to treat diabetes;

  
  


• 
  

  medicines to treat high blood pressure such as reserpine, guanethidine (Ismelin), methyldopa (Aldomet), and others; or

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

This list is not complete and other drugs may interact with phenylephrine nasal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More phenylephrine nasal resources

• Phenylephrine nasal Use in Pregnancy & Breastfeeding
• Phenylephrine nasal Drug Interactions
• Phenylephrine nasal Support Group
• 4 Reviews for Phenylephrine - Add your own review/rating

• Rhinall Advanced Consumer (Micromedex) - Includes Dosage Information


• Rhinall Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Compare phenylephrine nasal with other medications

• Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about phenylephrine nasal.

Formaldehyde Liquid

Formaldehyde 10%

Rx Only

INGREDIENTS

Active: Formaldehyde 10% Inactives: Purified Water, Polysorbate 20, Hydroxyethyl Cellulose, Methanol, Menta Piperita (Peppermint) Oil.

INDICATIONS

Drying agent for pre and post surgical removal of warts or where dryness is required. Safeguards against offensive odor and dries excessive moisture of feet.

Contraindications

Not to be used in patients known to be sensitive to any ingredients in Formaldehyde 10% Solution. Check skin for sensitivity to formaldehyde prior to application.

Precautions

FOR EXTERNAL USE ONLY. HARMFUL IF SWALLOWED. CONTACT A LOCAL POISON CONTROL CENTER IMMEDIATELY. KEEP OUT OF THE REACH OF CHILDREN. Avoid contact with and keep away from face, eyes, nose and mucous membranes. Check skin for sensitivity to formaldehyde prior to application since it may be irritating and sensitizing to the skin of some patients. If redness or irritation persists, consult your PODIATRIST, DERMATOLOGIST or PHYSICIAN.

Formaldehyde Liquid Dosage and Administration

Apply with roll-on applicator to affected areas once a day or as directed by a PODIATRIST, DERMATOLOGIST or PHYSICIAN. Do not shake bottle with the cap removed. When not is use, keep cap closed tightly.

How is Formaldehyde Liquid Supplied

Formaldehyde 10% is available in a 3 oz. (85.05 gm) plastic bottle with roll-on applicator. NDC 51991-512-19.

Dispense in original container.

Store at 25° C (77° F ); excursions permitted to 15° - 30°C (59° - 86° F). See USP Controlled Room Temperature. Protect from freezing.

Rx Only

Warning

Keep this and all medications out of the reach of children. In case of accidental overdose, seek professional assistance or contact a poison control center immediately.

All prescription substitutions using this product shall be pursuant to state statutes as applicable. This is not an Orange Book product.

Manufactured by:

Harmony Labs, Inc.

Kannapolis, NC 28083

Distributed by:

Breckenridge Pharmaceutical, Inc.

Boca Raton, FL 33487

Rev. 9/09

PRINCIPAL DISPLAY PANEL

Breckenridge

Pharmaceutical, Inc.

NDC 51991-512-19

Formaldehyde

10%

Drying Agent

Rx Only

3 oz. (85.05 gm)

FORMALDEHYDE  formaldehyde  liquid

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51991-512 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Formaldehyde (Formaldehyde) Formaldehyde 8.505 g  in 88.72059 mL

Inactive Ingredients Ingredient Name Strength Water   Polysorbate 20   Methyl Alcohol   Peppermint Oil

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 51991-512-19 1 BOTTLE In 1 CARTON contains a BOTTLE, WITH APPLICATOR 1 88.72059 mL In 1 BOTTLE, WITH APPLICATOR This package is contained within the CARTON (51991-512-19)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved other		01/01/2009

Labeler - Breckenridge Pharmaceutical, Inc. (150554335)

Establishment
Name	Address	ID/FEI	Operations
Harmony		784625760	MANUFACTURE

Revised: 10/2009Breckenridge Pharmaceutical, Inc.

More Formaldehyde Liquid resources

• Formaldehyde Liquid Side Effects (in more detail)
• Formaldehyde Liquid Use in Pregnancy & Breastfeeding
• Formaldehyde Liquid Support Group
• 0 Reviews · Be the first to review/rate this drug

Estraderm MX 25, 50, 75, 100

1. Name Of The Medicinal Product

Estraderm MX® 25

Estraderm MX® 50

Estraderm MX® 75

Estraderm MX® 100

2. Qualitative And Quantitative Composition

The active ingredient is estra-1, 3,5(10)-triene-3,17ß-diol (estradiol hemihydrate).

Patches contain 0.75 mg active substance corresponding to a surface area of 11cm².

Patches contain 1.50 mg active substance corresponding to a surface area of 22cm².

Patches contain 2.25 mg active substance corresponding to a surface area of 33cm².

Patches contain 3.0 mg active substance corresponding to a surface area of 44cm².

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Estraderm MX is a square-shaped, self-adhesive, transparent, transdermal patch for application to the skin surface. Each patch comprises an impermeable polyester backing film, an adhesive matrix containing estradiol and an oversized protective liner which is removed prior to application of the patch to the skin. Estraderm MX releases estradiol into the circulation via intact skin at a low rate for up to 4 days.

Cross section:

DOSAGE STRENGTHS	ESTRADERM MX 25
Nominal rate of estradiol release	25 micrograms /day
Estradiol content	0.75mg
Drug-releasing area	11 cm²
Imprint (on backing film)	Product logo CG GRG

DOSAGE STRENGTHS	ESTRADERM MX 50
Nominal rate of estradiol release	50 micrograms /day
Estradiol content	1.50mg
Drug-releasing area	22 cm²
Imprint (on backing film)	Product logo CG GSG

DOSAGE STRENGTHS	ESTRADERM MX 75
Nominal rate of estradiol release	75 micrograms /day
Estradiol content	2.25mg
Drug-releasing area	33 cm²
Imprint (on backing film)	Product logo CG HKH

DOSAGE STRENGTHS	ESTRADERM MX 100
Nominal rate of estradiol release	100 micrograms /day
Estradiol content	3.0mg
Drug-releasing area	44 cm²
Imprint (on backing film)	Product logo CG GTG

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. ( See section 5.1). (For MX 50 and MX 75 only).

(See also section 4.4)

The experience treating women older than 65 years is limited.

4.2 Posology And Method Of Administration

Estraderm MX 25 / 50 / 75 / 100 is an estrogen only patch.

In women with an intact uterus estrogen should be supplemented by sequential administration of a progestogen (e.g. medroxyprogesterone acetate 10mg, norethisterone 5mg, norethisterone acetate 1-5mg or dydrogesterone 20mg per day) to be taken at least on the last 12 days of each 4-week treatment cycle. Withdrawal bleeding usually occurs following 12 days or more of progesterone administration. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

Dosage

Adults and Elderly

Menopausal symptoms: For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used (see also section 4.4). Depending on the clinical response the dose can then be adjusted to the patient's individual needs. If, after three months, there is insufficient response in the form of alleviated symptoms, the dose can be increased. A maximum dose of 100 micrograms per day should not be exceeded.

Effects usually of estrogenic origin e.g. breast discomfort, water retention or bloating are often observed at the start of treatment, especially in patients receiving hormone replacement therapy for the first time. However, if symptoms persist for more than six weeks the dose should be reduced.

Postmenopausal osteoporosis: Estraderm MX 50 / 75 is recommended as an effective bone-sparing dose.

General instructions: Estraderm MX is administered as a continuous treatment (uninterrupted application twice weekly).

For most postmenopausal women not taking HRT Estraderm MX therapy may be started at any convenient time. However, for women with an intact uterus who are still menstruating regularly, commencement within 5 days of the onset of bleeding is recommended.

In women with an intact uterus transferring from a continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

In women transferring from a continuous-combined HRT regimen, or hysterectomised women transferring from other estrogen-only HRT treatment, treatment may be started on any convenient day.

Administration: Estraderm MX should be applied immediately after removal of the protective liner (see Figs.), to an area of clean, dry, and intact skin on the trunk below the waistline. The site chosen should be one at which little wrinkling of skin occurs during movement of the body, e.g. buttock. Estraderm MX should NOT be applied on or near the breasts.

Estraderm MX should be applied twice weekly on a continuous basis, each used patch being removed after 3-4 days and a fresh system applied to a slightly different site.

If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The interruption of treatment might increase the likelihood of recurrence of symptoms and include breakthrough spotting and bleeding.

In the event that a patch should fall off a new patch may be applied. The original treatment schedule should be continued.

The patch should not be exposed to sunlight.

Children

Estraderm MX should not be used in children

4.3 Contraindications

Estraderm MX should not be used by women with any of the following conditions:

• Known, past or suspected breast cancer

• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

• Known hypersensitivity to the active substance or to any of the excipients

• Porphyria

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical Examination / follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Estraderm MX, in particular:

• Leiomyoma (uterine fibroids) or endometriosis

• A history of, or risk factors for, thromboembolic disorders (see below)

• Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• A history of endometrial hyperplasia (see below)

• Epilepsy

• Asthma

• Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy

Endometrial hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk. Withdrawal bleeding usually occurs following the 12 days or more of progestogen administration.

For Estraderm MX 75 / 100 the endometrial safety of added progestogens has not been studied. Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see section 4.8 ).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.

One randomised controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (Body Mass Index> 30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contra-indicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

HRT should not be used to prevent cardiovascular disease.

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there only limited data from randomised controlled trials examining effect on cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years , the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5 to 10 years) use of estrogen–only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Other conditions

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Estraderm MX is increased.

Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). These effects may be less common with transdermal estradiol than with oral estrogens.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, patients who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuous exposure to the causative agent.

Although observations to date suggest that estrogens, including transdermal estradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.

Women should be advised that Estraderm MX is not a contraceptive, nor will it restore fertility. Women requiring contraception should be advised to use non

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens.

With transdermal HRT administration, the first-pass effect in the liver is avoided and, thus transdermally applied estrogens may be less affected by enzyme inducers than oral hormones.

Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effects and changes in the uterine bleeding profile

4.6 Pregnancy And Lactation

Pregnancy

Estraderm MX is not indicated during pregnancy. If pregnancy occurs during medication with Estraderm MX treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertant foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Lactation

Estraderm MX is not indicated during lactation

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Organ system class (e.g. MedDRA SOC level)	Common ADRS	Uncommon ADRs	Rare ADRs
Central nervous system	Headache.		Dizziness
Cardiovascular Disorders			Thromboembolic disorders, exacerbation of varicose veins, hypertension
Gastrointestinal disorder	Nausea, abdominal cramps, bloating		Abnormal liver function tests, cholestatic jaundice.
Skin and subcutaneous tissue disorders	Transient erythema and irritation at the site of application with or without pruritis		Contact dermatitis, pigmentation disorders, generalised pruritis and exanthema.
Reproductive system and breast disorders	Breast discomfort, breakthrough bleeding	*breast cancer
General disorders			Oedema and/or weight changes, leg pain, Anaphylactoid reactions

*Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 - 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:

• For users of estrogen-only replacement therapy

	• between 0 and 3 (best estimate = 1.5) for 5 years' use
	• between 3 and 7 (best estimate = 5) for 10 years' use.

• For users of estrogen plus progestogen combined HRT

	• between 5 and 7 (best estimate = 6) for 5 years' use
	• between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group,

• about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with estrogen alone and estrogen-progestogen treatments:

• Estrogen-dependent neoplasms, benign and malignant, e.g. endometrial cancer

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use

• Myocardial infarction and stroke

• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

• Gall bladder disease

• Probable dementia (see section 4.4)

4.9 Overdose

This is not likely due to the mode of administration.

Signs and Symptoms: Signs of acute estrogen overdosage may be either one of, or a combination of, breast discomfort, fluid retention and bloating or nausea.

Treatment: Overdosage can if necessary be reversed by removal of the patch(es).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: estrogens ATC code G 03 C A 03.

The active ingredient, synthetic 17β-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

The following to section 5.2 Pharmacokinetic Properties does NOT apply to Estraderm MX 25.

Estrogens prevent bone loss following menopause or ovariectomy. Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent.

Estraderm MX 100 is not recommended as the risk/benefit of the higher dose in osteoporosis has not been assessed in clinical studies. However, it may be used if necessary to control concurrent menopausal symptoms.

Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a prostagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

5.2 Pharmacokinetic Properties

Transdermal therapy with Estraderm MX delivers the physiological estrogen estradiol in unchanged form into the bloodstream via intact skin. Estraderm MX raises estradiol concentrations to levels similar to those found in the early to mid-follicular phase and maintains them over the application period of 3-4 days. The estradiol/estrone ratio is restored to premenopausal levels.

Within 8 hours after application of Estraderm MX 25, 50, 75 and 100 steady

With Estraderm MX 25, estradiol plasma levels half those observed with Estraderm MX 50 are measured. (Relates to MX 25 SPC only).

For Estraderm MX 100 plasma estradiol levels are slightly more that double those measured with Estraderm MX 50. (Relates to MX 100 SPC only).

Absorption rates may vary between individual patients. However, the plasma estradiol levels achieved with different sized systems have been shown to be proportional to the drug-releasing area of the dosage form.

After removal of the last system plasma estradiol levels return to baseline values in less than 24 hours.

The plasma elimination half

Estrone is further transformed to estradiol by the enzyme 17ß

The bulk of the conjugates are excreted in urine. Estrogen metabolites are also subject to enterohepatic circulation.

5.3 Preclinical Safety Data

Animal studies with estradiol have only shown effects which can be expected from an estrogenic substance.

Acute toxicity of estrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of estrogens in humans.

In experimental animals estradiol displayed an embryolethal effect already at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Acrylate, methacrylate, isopropyl palmitate, polyethylene terephthalate, ethylenevinylacetate copolymer, silicone coating (on the inner side of the protective release liner which is removed before patch application).

6.2 Incompatibilities

None known

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 25°C.

Keep out of the reach of children both before and after use.

6.5 Nature And Contents Of Container

Each system is individually heat sealed in a paper/aluminium/polyethylene foil pouch. Eight or twenty four Estraderm MX pouches are placed in an appropriately sized carton which comprises the finished product (one or three month's treatment respectively).

6.6 Special Precautions For Disposal And Other Handling

See Section 4.2. Exposure of Estraderm MX patches to ultra-violet light results in degradation of estradiol. Patches should not be exposed to sunlight. They should be applied immediately after removal from the pouch to skin sites covered by clothing.

After use, the Estraderm MX patch should be folded (adhesive surfaces pressed together) and discarded in such a way as to keep them out of the reach and sight of children.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd

Trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

8. Marketing Authorisation Number(S)

Estraderm MX 25:	PL 0101/0486
Estraderm MX 50:	PL 0101/0487
Estraderm MX 75:	PL 0101/0549
Estraderm MX 100:	PL 0101/0488

9. Date Of First Authorisation/Renewal Of The Authorisation

12 September 1997 / 10 February 2009

10. Date Of Revision Of The Text

24 July 2010

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