Alco may be available in the countries listed below.
Pseudoephedrine hydrochloride (a derivative of Pseudoephedrine) is reported as an ingredient of Alco in the following countries:
International Drug Name Search
Levalbuterol Inhalation Solution USP, Concentrate 1.25 mg (0.25%)*
*Potency expressed as Levalbuterol
PRESCRIBING INFORMATION
Rx Only
Levalbuterol Inhalation Solution, USP is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of Levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta2-adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). The chemical name for Levalbuterol HCl is (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
The molecular weight of Levalbuterol HCl is 275.8, and its molecular formula is C13H21NO3·HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
Levalbuterol Inhalation Solution, USP, Concentrate is supplied in 0.5 mL individually-wrapped unit-dose vials and should be diluted with sterile normal saline before administration by nebulization. Each 0.5 mL unit-dose vial contains 1.25 mg/0.5 mL (0.25%) of Levalbuterol HCl, USP (as 1.44 mg of Levalbuterol HCl), sodium chloride, USP to adjust tonicity and sulfuric acid NF to adjust the pH to 4.0 (3.3 to 4.5).
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 in 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. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol 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.
While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see WARNINGS). However, all 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.
Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that Levalbuterol has approximately 2-fold greater binding affinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, Levalbuterol HCl and racemic albuterol decreased the response to spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was ineffective. These results suggest that the bronchodilatory effects of racemic albuterol are attributable to the (R)-enantiomer.
Intravenous studies in rats with racemic 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 significance of these findings is unknown.
The inhalation pharmacokinetics of Levalbuterol Inhalation Solution, USP were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of Levalbuterol Inhalation Solution, USP and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000 compressor.
Following administration of a single 1.25 mg dose of Levalbuterol Inhalation Solution, USP exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 1.0). Following administration of a cumulative 5 mg dose of Levalbuterol Inhalation Solution, USP (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol were comparable (see Table 1.0).
| ||||
| Single Dose | Cumulative Dose | |||
| Levalbuterol Inhalation Solution, USP 1.25 mg | Racemic albuterol sulfate 2.5 mg | Levalbuterol Inhalation Solution, USP 5 mg | Racemic albuterol sulfate 10 mg | |
| Cmax (ng/mL) (R)-albuterol | 1.1 (0.45) | 0.8 (0.41)* | 4.5 (2.20) | 4.2 (1.51)* |
| Tmax (h)† (R)-albuterol | 0.2 (0.17, 0.37) | 0.2 (0.17, 1.50) | 0.2 (-0.18‡, 1.25) | 0.2 (-0.28‡ , 1.00) |
| AUC (ng●h/mL) (R)-albuterol | 3.3 (1.58) | 1.7 (0.99)* | 17.4 (8.56) | 16.0 (7.12)* |
| T½ (h) (R)-albuterol | 3.3 (2.48) | 1.5 (0.61) | 4.0 (1.05) | 4.1 (0.97) |
The pharmacokinetic parameters of (R)- and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data are presented in Table 2.0. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study are also presented in Table 2.0.
In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg Levalbuterol Inhalation Solution, USP were comparable to those following administration of 1.25 mg racemic albuterol sulfate inhalation solution.
When the same dose of 0.63 mg of Levalbuterol HCl, USP was given to children and adults, the predicted Cmax of (R)-albuterol in children was similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data support lower doses for children 6-11 years old compared with the adult doses (see DOSAGE AND ADMINISTRATION).
| ||||||
| Treatment | Children 6-11 years | Adults ≥ 12 years | ||||
| Levalbuterol Inhalation Solution, USP 0.31 mg | Levalbuterol Inhalation Solution, USP 0.63 mg | Racemic albuterol 1.25 mg | Racemic albuterol 2.5 mg | Levalbuterol Inhalation Solution, USP 0.63 mg | Levalbuterol Inhalation Solution, USP 1.25 mg | |
| AUC0-∞ (ng●hr/mL)* | 1.36 | 2.55 | 2.65 | 5.02 | 1.65† | 3.3‡ |
| Cmax (ng/mL)§ | 0.303 | 0.521 | 0.553 | 1.08 | 0.56† | 1.1‡ |
Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
The effect of hepatic impairment on the pharmacokinetics of Levalbuterol Inhalation Solution, USP has not been evaluated.
The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic albuterol clearance. Caution should be used when administering high doses of Levalbuterol Inhalation Solution, USP to patients with renal impairment.
In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of Levalbuterol Inhalation Solution, USP (0.31, 0.63, and 1.25 mg) and racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV1) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of Levalbuterol Inhalation Solution, USP and 2.5 mg of racemic albuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action (>15% increase FEV1 from baseline) after administration of 1.25 mg of Levalbuterol Inhalation Solution, USP. Systemic beta-adrenergic adverse effects were observed with all active doses and were generally dose-related for (R)-albuterol. Levalbuterol Inhalation Solution, USP at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.
In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of Levalbuterol HCl, 1.25 mg of (S)-albuterol, or placebo using a PARI LC Jet™ nebulizer. Racemic albuterol sulfate, Levalbuterol HCl, and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of Levalbuterol HCl was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.
In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV1) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of Levalbuterol Inhalation Solution, USP (four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).
The safety and efficacy of Levalbuterol Inhalation Solution, USP were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Levalbuterol HCl 0.63 mg, Levalbuterol HCl 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) was used on an as-needed basis as the rescue medication.
Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1.0) and day 29 (see Figure 2.0), 1.25 mg of Levalbuterol HCl demonstrated the largest mean percent change from baseline FEV1 compared with the other active treatments. A dose of 0.63 mg of Levalbuterol HCl and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV1 on both day 1 and day 29.
Figure 1.0: Mean Percent Change from Baseline FEV1 and Day 1, Adults and Adolescents ≥12 years old
Figure 2.0: Mean Percent Change from Baseline FEV1 on Day 29, Adults and Adolescents ≥12 years old
The mean time to onset of a 15% increase in FEV1 over baseline for Levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of Levalbuterol and approximately 6 hours after administration of 1.25 mg of Levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.
A multi-center, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV1 73% of predicted) (n =316). Following a 1-week placebo run-in, subjects were randomized to Levalbuterol HCl (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.
Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV1 curves for day 1 and day 21 are shown in Figure 3.0 and Figure 4.0, respectively. The onset of effect (time to a 15% increase in FEV1 over test day baseline) and duration of effect (maintenance of a >15% increase in FEV1 over test day baseline) of Levalbuterol were clinically comparable to those of racemic albuterol.
Figure 3.0: Mean Percent Change from Baseline FEV1 on Day 1, Children 6-11 Years of Age
Figure 4.0: Mean Percent Change from Baseline FEV1 on Day 21, Children 6-11 Years of Age
Levalbuterol Inhalation Solution, USP is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.
Levalbuterol Inhalation Solution, USP is contraindicated in patients with a history of hypersensitivity to Levalbuterol HCl or racemic albuterol.
Levalbuterol HCl, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; 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 the use of any beta-adrenergic bronchodilator.
Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-adrenergic agonist medications, Levalbuterol 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.
The action of Levalbuterol Inhalation Solution, USP may last up to 8 hours. Levalbuterol Inhalation Solution, USP should not be used more frequently than recommended. Do not increase the dose or frequency of dosing of Levalbuterol Inhalation Solution, USP without consulting your physician. If you find that treatment with Levalbuterol Inhalation Solution, USP becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are taking Levalbuterol Inhalation Solution, USP, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, headache, dizziness, and tremor or nervousness. If you are pregnant or nursing, contact your physician about the use of Levalbuterol Inhalation Solution, USP.
Effective and safe use of Levalbuterol Inhalation Solution, USP requires consideration of the following information in addition to that provided under Patient’s Instructions for Use:
Levalbuterol Inhalation Solution, USP single-use low-density polyethylene (LDPE) vials should be protected from light and excessive heat. Store in the protective foil pouch between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature]. Do not use after the expiration date stamped on the container. Open the foil pouch just prior to administration. Once the foil pouch is opened, the contents of the vial should be used immediately. Discard any vial if the solution is not colorless. Levalbuterol Inhalation Solution, USP, Concentrate should be diluted with sterile normal saline before administration by nebulization.
The drug compatibility (physical and chemical), efficacy, and safety of Levalbuterol Inhalation Solution, USP when mixed with other drugs in a nebulizer have not been established.
Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should be used with caution with Levalbuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
No carcinogenesis or impairment of fertility studies have been carried out with Levalbuterol HCl alone. However, racemic albuterol sulfate has been evaluated for its carcinogenic potential and ability to impair fertility.
In a 2-year study in Sprague-Dawley rats, racemic albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 2 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults and children on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 260 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults and children on a mg/m2 basis). In a 22-month study in the Golden hamster, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 35 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults and children on a mg/m2 basis).
Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Although Levalbuterol HCl has not been tested for clastogenicity, racemic albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults on a mg/m2 basis).
A reproduction study in New Zealand White rabbits demonstrated that Levalbuterol HCl was not teratogenic when administered orally at doses up to 25 mg/kg (approximately 110 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults on a mg/m2 basis). However, racemic albuterol sulfate has been shown to be teratogenic in mice and rabbits. A study in CD-1 mice given racemic 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 of Levalbuterol HCl for adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose of Levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose of Levalbuterol HCl 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 racemic albuterol sulfate was administered orally at a dose of 50 mg/kg (approximately 110 times the maximum recommended daily inhalation dose of Levalbuterol HCl for adults on a mg/m2 basis).
A study in which pregnant rats were dosed with radiolabeled racemic 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 Levalbuterol Inhalation Solution, USP in pregnant women. Because animal reproduction studies are not always predictive of human response, Levalbuterol Inhalation Solution, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
During marketing experience of racemic albuterol, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with racemic albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between racemic albuterol use and congenital anomalies has not been established.
Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of Levalbuterol Inhalation Solution, USP for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
Levalbuterol HCl has not been approved for the management of preterm labor. The benefit:risk ratio when Levalbuterol HCl is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.
Plasma levels of Levalbuterol after inhalation of therapeutic doses are very low in humans, but it is not known whether Levalbuterol is excreted in human milk.
Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of Levalbuterol Inhalation Solution, USP 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 Levalbuterol Inhalation Solution, USP is administered to a nursing woman.
The safety and efficacy of Levalbuterol Inhalation Solution, USP have been established in pediatric patients 6 years of age and older in one adequate and well-controlled clinical trial (see CLINICAL PHARMACOLOGY; Pharmacodynamics and Clinical Trials). Use of Levalbuterol HCl in children is also supported by evidence from adequate and well-controlled studies of Levalbuterol Inhalation Solution, USP in adults, considering that the pathophysiology and the drug’s exposure level and effects in pediatric and adult patients are substantially similar. Safety and effectiveness of Levalbuterol Inhalation Solution, USP in pediatric patients below the age of 6 years have not been established.
Data on the use of Levalbuterol Inhalation Solution, USP in patients 65 years of age and older are very limited. A very small number of patients 65 years of age and older were treated with Levalbuterol Inhalation Solution, USP in a 4-week clinical study (see CLINICAL PHARMACOLOGY; Clinical Trials) (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. There are insufficient data to determine if the safety and efficacy of Levalbuterol Inhalation Solution, USP are different in patients < 65 years of age and patients 65 years of age and older. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of Levalbuterol Inhalation Solution, USP. If clinically warranted due to insufficient bronchodilator response, the dose of Levalbuterol Inhalation Solution, USP may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose (see DOSAGE AND ADMINISTRATION).
Adverse events reported in ≥ 2% of patients receiving Levalbuterol Inhalation Solution, USP or racemic albuterol and more frequently than in patients receiving placebo in a 4-week, controlled clinical trial are listed in Table 3.0.
| Body System Preferred Term | Percent of Patients | |||
| Placebo (n=75) | Levalbuterol Inhalation Solution,USP 1.25 mg (n=73) | Levalbuterol Inhalation Solution, USP 0.63 mg (n=72) | Racemic Albuterol 2.5 mg (n=74) | |
| Body as a Whole | ||||
| Allergic reaction | 1.3 | 0 | 0 | 2.7 |
| Flu syndrome | 0 | 1.4 | 4.2 | 2.7 |
| Accidental injury | 0 | 2.7 | 0 | 0 |
| Pain | 1.3 | 1.4 | 2.8 | 2.7 |
| Back pain | 0 | 0 | 0 | 2.7 |
| Cardiovascular | ||||
| Tachychardia | 0 | 2.7 | 2.8 | 2.7 |
| Migraine | 0 | 2.7 | 0 | 0 |
| Digestive System | ||||
| Dyspepsia | 1.3 | 2.7 | 1.4 | 1.4 |
| Musculoskeletal System | ||||
| Leg cramps | 1.3 | 2.7 | 0 | 1.4 |
| Central Nervous System | ||||
| Dizziness | 1.3 | 2.7 | 1.4 | 0 |
| Hypertonia | 0 | 0 | 0 | 2.7 |
| Nervousness | 0 | 9.6 | 2.8 | 8.1 |
| Tremor | 0 | 6.8 | 0 | 2.7 |
| Anxiety | 0 | 2.7 | 0 | 0 |
| Respiratory System | ||||
| Cough increased | 2.7 | 4.1 | 1.4 | 2.7 |
| Infection viral | 9.3 | 12.3 | 6.9 | 12.2 |
| Rhinitis | 2.7 | 2.7 | 11.1 | 6.8 |
| Sinusitis | 2.7 | 1.4 | 4.2 | 2.7 |
| Turbinate edema | 0 | 1.4 | 2.8 | 0 |
The incidence of certain systemic beta-adrenergic adverse effects (e.g., tremor, nervousness) was slightly less in the Levalbuterol HCl 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.
Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the Levalbuterol Inhalation Solution, USP 1.25 mg and the racemic albuterol 2.5 mg groups (see Table 4.0). Changes in heart rate and plasma glucose were slightly less in the Levalbuterol Inhalation Solution, USP 0.63 mg group compared with the other acti
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Rx only
Each cycle of Levlite® 28 (levonorgestrel and ethinyl estradiol tablets, USP) consists of 21 pink active tablets each containing 0.100 mg levonorgestrel and 0.020 mg ethinyl estradiol; and seven white tablets—inert. The inactive ingredients are Calcium Carbonate USP, Corn Starch NF, Ferric Oxide/red/E 172 NF, Ferric Oxide/yellow/E 172 NF, Glycerin 85% Ph. Eur./DAB, Lactose Monohydrate NF, Magnesium Stearate NF, Montanglycol Wax (Wax E) DAB, Polyethylene glycol 6,000 NF, Povidone 25,000 USP, Povidone 700,000 USP, Pregelatinized Starch NF (Modified Starch), Sucrose NF, Talc USP and Titanium Dioxide, E 171 USP.
Levonorgestrel has a molecular weight of 312.4 and a molecular formula of C21H28O2. Ethinyl estradiol has a molecular weight of 296.4 and a molecular formula of C20H24O2. The structural formulas are as follows:
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol of Levlite in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the absolute bioavailability of ethinyl estradiol is about 40%.
After a single dose of three Levlite Tablets to 17 women under fasting conditions, the extents of absorption of levonorgestrel and ethinyl estradiol were 98.6% and 99.0%, respectively, relative to the same dose of the 2 drugs when given as a microcrystalline suspension in water. The effect of food on the bioavailability of Levlite Tablets following oral administration has not been evaluated.
The pharmacokinetics of levonorgestrel and ethinyl estradiol following daily administration of Levlite Tablets for 21 days per cycle for three cycles, were determined in 18 women. Estimates of the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol following single and multiple dose administration of Levlite Tablets are summarized in Table I. Mean levonorgestrel and ethinyl estradiol levels after a single dose and on day 21 at steady state are shown in Figure I.
The pharmacokinetics of total levonorgestrel are non-linear due to an increase in binding to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Increased binding of levonorgestrel to SHBG leads to decreased clearance of levonorgestrel. Observed maximum levonorgestrel concentrations increased from day 1 to day 21 of the 1st and 3rd cycles by 66% and 83%, respectively.
FIGURE I Mean Levonorgestrel Concentrations in Serum after single dose and on Day 21 of Cycles 1 and 3
Mean Ethinyl Estradiol Concentrations in Serum after single dose and on Day 21 of Cycles 1 and 3
In calculating the mean concentration for ethinyl estradiol, any individual subject value below the quantifiable limit (i.e., 20 pg/mL) was converted to 0; and the 0 values were included for calculation of the mean concentration. Table I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.
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| Levonorgestrel | ||||||
Day (cycle) | Cmax* ng/mL | tmax† h | AUC‡ ng•h/mL | CL/F§ mL/min/kg | Vz¶ L | SHBG# nmol/L |
| 1 | 2.36 (0.79) | 1.3 (0.4) | 29.2 (10.0) | 1.0 (0.3) | 129 (46) | 64.5 (22.0) |
AUC (0-24h)Þ ng•h/mL | ||||||
| 21 (1) | 4.04 (2.08) | 1.0 (0.3) | 43.8 (22.4) | 0.73 (0.34) | 106 (42) | 94.7 (37.4) |
| 21 (3) | 4.53 (1.94) | 1.0 (0.3) | 49.5 (24.5) | 0.65 (0.33) | 96 (35) | 107.4 (45.8) |
| |||
| Ethinyl Estradiol | |||
Day (cycle) | Cmax* pg/mL | tmax† h | AUC(0-24)‡ pg•h/mL |
| 1 | 49.5 (13.4) | 1.5 (0.4) | 298 (215) |
| 21 (1) | 66.2 (29.5) | 1.4 (0.4) | 596 (494) |
| 21 (3) | 58.1 (19.3) | 1.4 (0.3) | 417 (289) |
Levonorgestrel in serum is primarily bound to SHBG. Protein binding values for levonorgestrel are provided in Table II. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.
| Parameter | Single Dose | Cycle 2 | Cycle 4 |
| % free | 1.11 (0.27) | 0.79 (0.22) | 0.80 (0.23) |
| % SHBG-bound | 64.5 (8.54) | 75.6 (6.59) | 74.7 (7.89) |
| % albumin-bound | 34.4 (8.28) | 23.6 (6.41) | 24.5 (7.67) |
The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation in levonorgestrel concentrations among users.
Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in the rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
The elimination half-life for levonorgestrel after a single dose of Levlite® is 25.4 ± 9.7 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. The elimination half-life of ethinyl estradiol has been reported to be between 15 and 25 hours.
No formal studies have evaluated the effect of hepatic disease on the disposition of Levlite. However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have evaluated the effect of renal disease on the disposition of Levlite.
Interactions between ethinyl estradiol and other drugs have been reported in the literature.
Interactions with Absorption. Diarrhea may increase gastrointestinal motility and reduce hormone absorption. Similarly, any drug which reduces gut transit time may reduce hormone concentrations in the blood.
Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal wall. Therefore, drugs which act as competitive inhibitors for sulfation in the gastrointestinal wall may increase ethinyl estradiol bioavailability.
Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (e.g., rifampin, barbiturates, phenylbutazone, phenytoin, griseofulvin).
Some clinical reports suggest that enteroheptic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinyl estradiol concentrations (e.g., ampicillin, tetracycline).
Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased or decreased, respectively (e.g., cyclosporin, theophylline).
Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table III lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. | |||
| |||
% of Women Experiencing an Accidental Pregnancy within the First Year of Use | % of Women Continuing Use at One Year* | ||
Method (1) | Typical Use† (2) | Perfect Use‡ (3) | (4) |
| Chance § | 85 | 85 | |
| Spermicides¶ | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation method | 3 | ||
| Sympto-thermal# | 2 | ||
| Post Ovulation | 1 | ||
| Withdrawal | 19 | 4 | |
CapÞ | |||
| Parous women | 40 | 26 | 42 |
| Nulliparous women | 20 | 9 | 56 |
Sponge | |||
| Parous women | 40 | 20 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| DiaphragmÞ | 20 | 6 | 56 |
Condomß | |||
| Female (Reality) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| progestin only | 0.5 | ||
| combined | 0.1 | ||
IUD | |||
| Progesterone T | 2 | 1.5 | 81 |
| Copper T 380A | 0.8 | 0.6 | 78 |
| Lng 20 | 0.1 | 0.1 | 81 |
| Depo Provera | 0.3 | 0.3 | 70 |
| Norplant and Norplant-2 | 0.05 | 0.05 | 88 |
| Female sterilization | 0.5 | 0.5 | 100 |
| Male sterilization | 0.15 | 0.10 | 100 |
Oral contraceptives should not be used in women who currently have the following conditions:
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiologic methods.
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table IV) among women who use oral contraceptives.
| Adapted from P.M. Layde and V. Beral | ||||
| AGE | EVER- USERS NON- SMOKERS | EVER- USERS SMOKERS | CONTROLS NON- SMOKERS | CONTROL SMOKERS |
| 15–24 | 0.0 | 10.5 | 0.0 | 0.0 |
| 25–34 | 4.4 | 14.2 | 2.7 | 4.2 |
| 35–44 | 21.5 | 63.4 | 6.4 | 15.2 |
| 45+ | 52.4 | 206.7 | 11.4 | 27.9 |
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. ln particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in "WARNINGS"). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in the relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued from at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed.
Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor, for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.
ln a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which provides satisfactory results in the individual.
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. ln a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women aged 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. ln another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table V). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth.
The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's—but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
| Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983. | ||||||
| ||||||
| Method of Control and Outcome | 15–19 | 20–24 | 25–29 | 30–34 | 35–39 | 40–44 |
| No fertility control methods* | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
| Oral contraceptives nonsmoker† | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
| Oral contraceptives smoker† | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
| lUD† | 0.8 | 0.8 | 1.0 | 1.0 | 1.4 | 1.4 |
| Condom* | 1.1 | 1.6 | 0.7 | 0.2 | 0.3 | 0.4 |
| Diaphragm/spermicide* | 1.9 | 1.2 | 1.2 | 1.3 | 2.2 | 2.8 |
| Periodic abstinence* | 2.5 | 1.6 | 1.6 | 1.7 | 2.9 | 3.6 |
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses. The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use. A few studies have shown a slightly increased relative risk of developing breast cancer, although the methodology of these studies, which included differences in examination of users and nonusers and differences in age at start of use, has been questioned.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
ln spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been
