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Thursday, September 29, 2016

Risperidone Orally Disintegrating

FULL PRESCRIBING INFORMATION

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See WARNINGS AND PRECAUTIONS (5.1).]

Indications and Usage for Risperidone Orally Disintegrating

Schizophrenia

Adults

Risperidone is indicated for the acute and maintenance treatment of schizophrenia [see CLINICAL STUDIES (14.1)].

Adolescents

Risperidone is indicated for the treatment of schizophrenia in adolescents aged 13 to 17 years [see CLINICAL STUDIES (14.1)].

Bipolar Mania

Monotherapy - Adults

Risperidone is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10 to 17 years [see CLINICAL STUDIES (14.2)].

Combination Therapy – Adults

The combination of risperidone with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see CLINICAL STUDIES (14.3)].

Irritability Associated with Autistic Disorder

Pediatrics

Risperidone is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5 to 16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see CLINICAL STUDIES (14.4)].

Risperidone Orally Disintegrating Dosage and Administration

Schizophrenia

Adults

Usual Initial Dose

Risperidone can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1 to 2 mg/day, as tolerated, to a recommended dose of 4 to 8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 to 16 mg/day [see CLINICAL STUDIES (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see CLINICAL STUDIES (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.

Adolescents

The dosage of risperidone should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. There are no controlled data to support the longer term use of risperidone beyond 8 weeks in adolescents with schizophrenia. The physician who elects to use risperidone for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

Bipolar Mania

Usual Dose

Adults

Risperidone should be administered on a once daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 to 6 mg per day [see CLINICAL STUDIES (14.2, 14.3)]. Risperidone doses higher than 6 mg per day were not studied.

Pediatrics

The dosage of risperidone should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)

The safety and effectiveness of risperidone in pediatric patients with autistic disorder less than 5 years of age have not been established.

The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily.

Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg.

In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see CLINICAL STUDIES (14.4)]) received doses of risperidone between 0.5 mg and 2.5 mg per day. The maximum daily dose of risperidone in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or 3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg

Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

Dosage in Special Populations

The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.

Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate risperidone than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see CLINICAL PHARMACOLOGY (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see WARNINGS AND PRECAUTIONS (5.2, 5.7, 5.17)]. If a once daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice daily regimen for 2 to 3 days at the target dose. Subsequent switches to a once daily dosing regimen can be done thereafter.

Co-Administration of Risperidone with Certain Other Medications

Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of risperidone treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see DRUG INTERACTIONS (7.11)].

Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5 to 2.8 fold and 3 to 9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see DRUG INTERACTIONS (7.10)].

Directions for Use of Risperidone Orally Disintegrating Tablets

Tablet Accessing

Risperidone Orally Disintegrating Tablets 0.25 mg

Risperidone Orally Disintegrating Tablets 0.25 mg are supplied in cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets.

Risperidone Orally Disintegrating Tablets 0.5 mg and 1 mg

Risperidone Orally Disintegrating Tablets 0.5 mg and 1 mg are supplied in cartons of 28 tablets with 7 blister packs of 4 (2x2) tablets, and in cartons of 30 tablets with 5 blister packs of 6 (3x2) tablets.

Risperidone Orally Disintegrating Tablets 2 mg, 3 mg and 4 mg

Risperidone Orally Disintegrating Tablets 3 mg and 4 mg are supplied in cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets.

Do not open the blister until ready to administer. For single tablet removal, separate one of the four or six blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet.

Tablet Administration

Using dry hands, remove the tablet from the blister unit and immediately place the entire Risperidone Orally Disintegrating Tablet on the tongue. The Risperidone Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. Risperidone Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.

Dosage Forms and Strengths

Risperidone Orally Disintegrating Tablets are available in the following strengths: 0.25 mg,

0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. All are round shaped, white in color and imprinted with “P” on one side and either “212”, “311”, “315”, “401”, “402”, or “403” on the other side according to their respective strengths.

Contraindications

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, risperidone is contraindicated in patients with a known hypersensitivity to the product.

Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for the treatment of dementia-related psychosis [see BOXED WARNING].

Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1).]

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone , should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 1a.

Table 1a. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
	Placebo	Risperidone 1-8 mg/day	Risperidione >8-16 mg/day
		Mean change from baseline (mg/dL)
	N=555	N=748	N=164
Serum Glucose	-1.4	0.8	0.6
		Proportion of patients with shifts
Serum Glucose (<140 mg/dL to ≥200 mg/dL)	0.6% (3/525)	0.4% (3/702)	0% (0/158)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and +4.1 mg/dL at Week 48 (N=50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 1b.

Table 1b. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania ( 10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)
	Placebo	Risperidone 0.5-6mg/day
	Mean change from basline (mgdL)
	N=76	N=135
Serum Glucose	-1.3	2.6
	Proportion of patients with shifts
Serum Glucose (>100mg/dL to ≥126 mg/dL)	0% (0/64)	0.8% (1/120)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2mg/dL at Week 24 (N=119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 2a.

Table 2a. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
	Placebo	Risperidone 1-8 mg/day	Risperidone > 8-16 mg/day
		Mean change from baseline (mg/dL)
Cholesterol	N=559	N=742	N=156
Change from baseline	0.6	6.9	1.8
Triglycerides	N=183	N=307	N=123
Change from baseline	-17.4	-4.9	-8.3
		Proportion of patients with shifts
Cholesterol (<200mg/dL to ≥240 mg/dL)	2.7% (10/368)	4.3% (22/516)	6.3% (6/96)
Triglycerides (<500mg/dL to ≥500 mg/dL)	1.1% (2/180)	2.7% (8/301)	2.5% (3/121)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (N=231) and + 5.5 mg/dL at Week 48 (N=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (N=52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 2b.

Table 2b. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed- Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
	Placebo	Risperidone 0.5 - 6 mg/day
	Mean change from baseline (mg/dL)
Cholesterol	N=74	N=133
Change from baseline	0.3	-0.3
LDL	N=22	N=22
Change from baseline	3.7	0.5
HDL	N=22	N=22
Change from baseline	1.6	-1.9
Triglycerides	N=77	N=138
Change from baseline	-9.0	-2.6
	Proportion of patients with shifts
Cholesterol (170 mg/dL to ≥200 mg/dL)	2.4% (1/42)	3.8% (3/80)
LDL (110 mg/dL to ≥130 mg/dL)	0% (0/16)	0% (0/16)
HDL (≥40 mg/dL to < 40mg/dL)	0% (0/19)	10% (2/20)
Triglycerides (<150 mg/dL to ≥200 mg/dL)	1.5% (1/65)	7.1% (8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (N=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (N=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (N=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (N=120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8-week, fixed- or flexible-dose studies in adults with schizophrenia or bipolar mania are presented in Table 3a.

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects ≥ 7% Gain in Body Weight from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adults Subjects With Schizophrenia or Bipolar Mania
	Placebo (N=597)	Risperidone 1-8 mg/day (N=769)	Risperidone >8 - 16 mg/day (N=158)
Weight (kg)
Change from baseline	-0.3	0.7	2.2
Weight Gain
≥7% increase from baseline	2.9%	8.7%	20.9%

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3kg at Week 24 (N=395) and +5.3kg at Week 48 (N=203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7 gain in body weight from 9 placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 3b.

Table 3 b. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥ 7% Gain in Body Weight from Nine Placebo-Controlled, 3- to 8-Week, Fixed- Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder ( 5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)
	Placebo (N=375)	Risperidone 0.5-6 mg/day (N=448)
Weight (kg)
Change from baseline	0.6	2.0
Weight Gain
≥7% increase from baseline	6.9%	32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (N=748) and +8.0 kg at Week 48 (N=242).

Hyperprolactinemia

As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long- standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see NONCLINICAL TOXICOLOGY (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Orthostatic Hypotension

Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see DOSAGE AND ADMINISTRATION (2.1, 2.4)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication.

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropinia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue risperidone and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse event associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely.

Seizures

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1).]

Priapism

Priapism has been reported during postmarketing surveillance [see ADVERSE REACTIONS (6.9)]. Severe priapism may require surgical intervention.

Thrombotic Thrombocytopenic Purpura (TTP)

A single case of TTP was reported in a 28 year old female patient receiving oral risperidone in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to risperidone therapy is unknown.

Body Temperature Regulation

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

Antiemetic Effect

Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor.

Suicide

The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for risperidone should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.

Use in Patients with Concomitant Illness

Clinical experience with risperidone in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including risperidone, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

Caution is advisable in using risperidone in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were

Lazanda Spray

Pronunciation: FEN-ta-nil
Generic Name: Fentanyl
Brand Name: Lazanda

Lazanda Spray can be harmful or fatal if taken by children, patients for whom it has not been prescribed, or patients who are not tolerant to narcotic (opioid) pain medicine. Keep Lazanda Spray out of the reach of children.

Lazanda Spray is only for breakthrough pain caused by cancer in patients 18 years old and older who are already using and are tolerant to around-the-clock narcotic pain medicine. Severe and sometimes fatal breathing problems can occur in patients using Lazanda Spray, especially in patients who are not already using other narcotic medicines or patients who are taking certain other medicines. Ask your health care provider if Lazanda Spray may interact with other medicines that you take. Do not use Lazanda Spray for short-term pain (including headache, dental pain, or migraine) or for pain that occurs after surgery or injuries.

Do NOT take more than the recommended dose or use more often than prescribed. You must wait at least 2 hours after your last dose of Lazanda Spray before treating a NEW episode of breakthrough pain with Lazanda Spray.

Do not switch between Lazanda Spray and other medicines that contain fentanyl without first talking with your doctor. Different types of medicines that contain fentanyl may release different amounts of Lazanda Spray into your body. This may cause severe and possibly fatal overdose. Talk with your doctor or pharmacist for more information.

Lazanda Spray is used for:

Managing breakthrough pain in cancer patients 18 years of age and older who are already using and are tolerant to around-the-clock narcotic pain medicines.

Lazanda Spray is a narcotic (opioid) analgesic. It works in the brain to decrease pain.

Do NOT use Lazanda Spray if:

you are allergic to any ingredient in Lazanda Spray or to any similar medicine (eg, sufentanil)

you have not been taking other narcotic pain medicines (eg, morphine, codeine) on a regular schedule

you have mild or short-term pain, including pain from injuries, surgery, dental pain, headache, or migraine

you are taking sibutramine or sodium oxybate (GHB)

you are taking or have taken a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the past 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Lazanda Spray:

Some medical conditions may interact with Lazanda Spray. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

if you have a history of mental or mood problems (eg, depression), hallucinations, or suicidal thoughts or actions

if you have severe drowsiness; lesions, growths, or increased pressure in the brain; or a recent head injury

if you have lung or breathing problems (eg, asthma, slow or difficult breathing, chronic obstructive pulmonary disease [COPD]), urinary blockage, heart problems (eg, slow or irregular heartbeat, ventricle problems), liver or kidney disease, inflammation in the mouth, an enlarged prostate or benign prostatic hypertrophy (BPH), stomach or bowel problems (eg, constipation, inflammatory bowel disease, pseudomembranous colitis, stomach pain), an underactive thyroid, low blood pressure, or seizures

if you or a family member has a history of alcohol, narcotic, or other substance abuse or dependence

if you have been very ill, have a fever, have poor health or nutrition, or have had a recent surgery (eg, stomach or bowel surgery)

if you stop taking your around-the-clock narcotic pain medicine

Some MEDICINES MAY INTERACT with Lazanda Spray. Tell your health care provider if you are taking any other medicines, especially any of the following:

Amiodarone, antihistamines (eg, diphenhydramine), aprepitant, azole antifungals (eg, ketoconazole), benzodiazepines (eg, diazepam), calcium channel blockers (eg, diltiazem, verapamil), cimetidine, macrolides (eg, erythromycin, clarithromycin), MAOIs (eg, phenelzine), nefazodone, other opioid medicines (eg, oxycodone), phenothiazines (eg, chlorpromazine), protease inhibitors (eg, ritonavir), skeletal muscle relaxants (eg, cyclobenzaprine), sleep medicines (eg, zolpidem), sodium oxybate (GHB), or telithromycin because they may increase the risk of Lazanda Spray's side effects, including serious breathing problems, severe light-headedness or dizziness, or severe drowsiness

Serotonin reuptake inhibitors (eg, fluoxetine) or sibutramine because a severe reaction that may include fever, rigid muscles, blood pressure changes, mental changes, confusion, irritability, agitation, delirium, and coma may occur

Mixed agonist/antagonist analgesics (eg, pentazocine, buprenorphine, butorphanol), nalmefene, naloxone, or naltrexone because they may decrease Lazanda Spray's effectiveness and withdrawal symptoms may occur

Barbiturates (eg, phenobarbital), carbamazepine, corticosteroids (eg, prednisone), efavirenz, modafinil, certain nasal decongestants (eg, oxymetazoline), nevirapine, oxcarbazepine, phenytoin, pioglitazone, rifamycins (eg, rifampin), St. John's wort, or troglitazone because they may decrease Lazanda Spray's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Lazanda Spray may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Lazanda Spray:

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

Lazanda Spray comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Lazanda Spray refilled.

When you first start to use Lazanda Spray, your doctor may adjust your dose to find the dose that controls your pain the best. Be sure to follow the directions for using Lazanda Spray provided by your doctor. Do NOT change your dose of Lazanda Spray without checking with your doctor.

Do not remove Lazanda Spray from the child-resistant container until you are ready to use it. Replace the bottle in the child-resistant container between doses of Lazanda Spray. Keep Lazanda Spray, both unopened and opened bottles, in the child-resistant container and out of the reach of children at all times.

Before you use a new bottle for the first time, you will need to prime it. Prime the bottle according to the directions in the medication guide. Contact your pharmacist if you are unsure how to prime the bottle.

To be sure that Lazanda Spray is ready to be used, be sure that you see either a green bar or a number in the counting window.

If you have a runny nose, blow your nose before using Lazanda Spray.

To use a dose of Lazanda Spray, remove the protective cap from the tip and sit up with your head upright. Hold the bottle with your thumb on the bottom, and your first and middle fingers on the finger grips. Place the tip of the spray container into the nose and point it toward the bridge of your nose. Using a finger from your other hand, press against the opposite nostril to close it off. Press down on the finger grips until you hear a click. Breathe in gently through your nose and out through your mouth 1 time after spraying. Do not sniff after spraying Lazanda Spray in your nose.

If your dose is equal to 2 sprays of Lazanda Spray, repeat these steps in the other nostril. Do NOT use more than 1 dose of Lazanda Spray per episode of breakthrough pain.

Stay seated for at least 1 minute after using Lazanda Spray. Avoid blowing your nose for at least 30 minutes after each spray.

After you are done using your dose, replace the protective cap on the tip of the bottle and return the bottle to the child-resistant container.

After each spray, the number in the counting window will increase by 1. When you see a red number 8 in the counting window, the bottle is finished. You may still see medicine in the bottle but there is not enough for a full dose.

If your breakthrough pain does NOT get better within 30 minutes after your dose, follow your doctor's directions about taking other medicine to manage your pain. If your breakthrough pain does not get better, contact your doctor.

Wait at least 2 hours after your last dose of Lazanda Spray before treating a NEW episode of breakthrough pain. If you have more than 4 episodes of breakthrough pain per day, tell your doctor.

Dispose of Lazanda Spray if you have used 8 sprays from a bottle, if it has been 5 days since you last used it, or if it has been 14 days since you primed it. If Lazanda Spray is no longer needed, dispose of it as soon as possible. Ask your doctor or pharmacist how to dispose of Lazanda Spray properly.

Check with your doctor before including grapefruit or grapefruit juice in your diet while you use Lazanda Spray.

Lazanda Spray is usually used as needed. If you forget to use a dose of Lazanda Spray and you still have pain, use it when you remember and as directed by your doctor. Do not take 2 doses at once.

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

Important safety information:

Lazanda Spray may cause drowsiness or dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use Lazanda Spray with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Do not drink alcohol while you are using Lazanda Spray.

Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Lazanda Spray; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.

Lazanda Spray may cause dizziness, light-headedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.

Constipation is a common side effect of Lazanda Spray. Talk with your doctor about using laxatives or stool softeners while you use Lazanda Spray to prevent or treat constipation. It is also important to maintain a diet adequate in fiber, drink plenty of water, and exercise to prevent constipation.

Do NOT take more than the recommended dose, use more often than prescribed, or suddenly stop using Lazanda Spray without checking with your doctor.

Tell your doctor or dentist that you use Lazanda Spray before you receive any medical or dental care, emergency care, or surgery.

Contact your doctor if your pain is not relieved or if it worsens after you use Lazanda Spray. Contact your doctor if your usual dose stops providing pain relief. Be sure to tell your doctor or health care provider how your pain is responding to Lazanda Spray so that your dose can be adjusted if needed.

Do not switch between Lazanda Spray and other medicines that contain fentanyl without first talking to your doctor. Different types of medicines that contain fentanyl may release different amounts of Lazanda Spray into your body. This may cause severe and possibly fatal overdose. Discuss any questions or concerns with your doctor or pharmacist.

Use Lazanda Spray with caution in the ELDERLY; they may be more sensitive to its effects, especially breathing problems.

Lazanda Spray can be harmful, even fatal, if used in CHILDREN. Keep Lazanda Spray out of the reach of children.

PREGNANCY and BREAST-FEEDING: Lazanda Spray may cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Lazanda Spray while you are pregnant. Lazanda Spray is found in breast milk. Do not breast-feed while using Lazanda Spray.

When used for long periods of time or at high doses, Lazanda Spray may not work as well and may require higher doses to obtain the same effect as when first taken. This is known as TOLERANCE. Talk with your doctor if Lazanda Spray stops working well. Do not take more than prescribed.

When used for long periods of time or at high doses, some people develop a need to continue taking Lazanda Spray. This is known as DEPENDENCE or "addiction."

If you suddenly stop taking Lazanda Spray, you may experience WITHDRAWAL symptoms, including anxiety; diarrhea; fever, runny nose, or sneezing; goose bumps and abnormal skin sensations; nausea; vomiting; pain; rigid muscles; rapid heartbeat; seeing, hearing, or feeling things that are not there; shivering or tremors; sweating; and trouble sleeping.

Possible side effects of Lazanda Spray:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dizziness; drowsiness; headache; nasal discomfort; nausea; stuffy or runny nose; taste changes; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue); chest pain; confusion; coughing up blood; difficult or painful urination; fainting; fast, slow, or irregular heartbeat; fever; hallucinations; mood or mental changes (eg, depression); seizures; severe drowsiness; severe or persistent dizziness or headache; severe or persistent stomach pain; shortness of breath; slowed, shallow, or trouble breathing; unusual weakness or tiredness.

If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Lazanda side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include loss of consciousness; muscle rigidity; pinpoint pupils; severe drowsiness or dizziness; slow or shallow breathing; very slow or weak heartbeat.

Proper storage of Lazanda Spray:

Store Lazanda Spray below 77 degrees F (25 degrees C). Store in the original package, away from heat, moisture, and light. Do not store in the bathroom. Do not freeze. Keep Lazanda Spray out of the reach of children and away from pets.

General information:

If you have any questions about Lazanda Spray, please talk with your doctor, pharmacist, or other health care provider.

Lazanda Spray is to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Lazanda Spray. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Lazanda resources

Lazanda Side Effects (in more detail)
Lazanda Use in Pregnancy & Breastfeeding
Lazanda Drug Interactions
Lazanda Support Group
0 Reviews for Lazanda - Add your own review/rating

Compare Lazanda with other medications

Breakthrough Pain

Benzylpenicillin Cooper

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Benzylpenicillin

Benzylpenicillin sodium (a derivative of Benzylpenicillin) is reported as an ingredient of Benzylpenicillin Cooper in the following countries:

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Minims Phenylephrine Hydrochloride
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Phenylephrine

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SPC

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Atropin

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Atropine

Atropine sulfate (a derivative of Atropine) is reported as an ingredient of Atropin in the following countries:

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Almatol

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Clopidogrel

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Diazepam

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Acutol

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Hyperkinetic Syndrome of Childhood Medications

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Alpheus

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Simvastatin

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Ceftin

Generic Name: cefuroxime (SEF ue ROX eem)

Brand Names: Ceftin

What is cefuroxime?

Cefuroxime is in a group of drugs called cephalosporin (SEF a low spor in) antibiotics. It works by fighting bacteria in your body.

Cefuroxime is used to treat many kinds of bacterial infections, including severe or life-threatening forms.

Cefuroxime may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about cefuroxime?

Do not take this medication if you are allergic to cefuroxime, or to similar antibiotics, such as Cefzil, Keflex, Omnicef, and others.

Before taking this medication, tell your doctor if you are allergic to any drugs (especially penicillin). Also tell your doctor if you have liver or kidney disease, diabetes, a history of intestinal problems, or if you are malnourished.

Cefuroxime can make birth control pills less effective, which may result in pregnancy. Tell your doctor if you are taking birth control pills to prevent pregnancy. You may need to use another form of birth control during treatment with cefuroxime.

Take this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cefuroxime will not treat a viral infection such as the common cold or flu.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use any medicine to stop the diarrhea unless your doctor has told you to.

This medication can cause you to have false results with certain medical tests, including urine glucose (sugar) tests. Tell any doctor who treats you that you are using cefuroxime.

What should I discuss with my health care provider before taking cefuroxime?

Do not take this medication if you are allergic to cefuroxime, or to other cephalosporin antibiotics, such as:

cefaclor (Raniclor);

cefadroxil (Duricef);

cefazolin (Ancef);

cefdinir (Omnicef);

cefditoren (Spectracef);

cefpodoxime (Vantin);

cefprozil (Cefzil);

ceftibuten (Cedax);

cephalexin (Keflex); or

cephradine (Velosef).

Before taking cefuroxime, tell your doctor if you are allergic to any drugs (especially penicillins), or if you have:

kidney disease;

liver disease;

a history of intestinal problems, such as colitis;

diabetes; or

if you are malnourished.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take cefuroxime.

The oral suspension (liquid) form of cefuroxime may contain phenylalanine. Talk to your doctor before using this form of cefuroxime if you have phenylketonuria (PKU).

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Cefuroxime can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take cefuroxime?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

You may take cefuroxime tablets with or without meals.

Cefuroxime oral suspension (liquid) must be taken with food. Shake the oral liquid well just before you measure a dose. To be sure you get the correct dose, measure the liquid with a marked measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one. If you switch from using the tablet form to using the oral suspension (liquid) form of cefuroxime, you may not need to use the same exact dosage in number of milligrams. The medication may not be as effective unless you use the exact form and strength your doctor has prescribed. Use this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cefuroxime will not treat a viral infection such as the common cold or flu.

This medication can cause you to have false results with certain medical tests, including urine glucose (sugar) tests. Tell any doctor who treats you that you are using cefuroxime.

Store cefuroxime tablets at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use. Store cefuroxime oral liquid in the refrigerator. Do not allow it to freeze. Throw away any unused medication that is older than 10 days.

What happens if I miss a dose?

Take the medication as soon as you remember the missed dose. If it is almost time for your next dose, skip the missed dose and use the medicine at your next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. Overdose symptoms may include seizure (black-out or convulsions).

What should I avoid while taking cefuroxime?

Cefuroxime 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. Call your doctor at once if you have any of these serious side effects:

diarrhea that is watery or bloody;

fever, chills, body aches, flu symptoms;

chest pain, fast or pounding heartbeats;

unusual bleeding;

blood in your urine;

seizure (convulsions);

pale or yellowed skin, dark colored urine, fever, confusion or weakness;

jaundice (yellowing of the skin or eyes);

fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;

skin rash, bruising, severe tingling, numbness, pain, muscle weakness;

increased thirst, loss of appetite, swelling, weight gain, feeling short of breath; or

painful or difficult urination, urinating less than usual or not at all.

Less serious side effects may include:

nausea, vomiting, stomach pain, mild diarrhea, gas, upset stomach;

cough, stuffy nose;

stiff or tight muscles, muscle pain;

joint pain or swelling;

headache, drowsiness;

feeling restless, irritable, or hyperactive;

white patches or sores inside your mouth or on your lips;

unusual or unpleasant taste in your mouth;

diaper rash in an infant taking liquid cefuroxime;

mild itching or skin rash; or

vaginal itching or discharge.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect cefuroxime?

Before taking cefuroxime, tell your doctor if you are taking any of the following drugs:

probenecid (Benemid);

a blood thinner such as warfarin (Coumadin);

a medication that reduces stomach acid, such as an antacid, or cimetidine (Tagamet), famotidine (Pepcid), omeprazole (Prilosec), ranitidine (Zantac), and others; or

a diuretic (water pill) such as bumetanide (Bumex), furosemide (Lasix), indapamide (Lozol), hydrochlorothiazide (HCTZ, HydroDiuril, Hyzaar, Lopressor, Vasoretic, Zestoretic), metolazone (Mykrox, Zarxolyn), spironolactone (Aldactazide, Aldactone), torsemide (Demadex), and others.

This list is not complete and there may be other drugs that can interact with cefuroxime. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start taking a new medication without telling your doctor.

More Ceftin resources

Ceftin Side Effects (in more detail)
Ceftin Use in Pregnancy & Breastfeeding
Drug Images
Ceftin Drug Interactions
Ceftin Support Group
14 Reviews for Ceftin - Add your own review/rating

Ceftin Prescribing Information (FDA)

Ceftin Consumer Overview

Ceftin Advanced Consumer (Micromedex) - Includes Dosage Information

Ceftin MedFacts Consumer Leaflet (Wolters Kluwer)

Cefuroxime MedFacts Consumer Leaflet (Wolters Kluwer)

Cefuroxime Professional Patient Advice (Wolters Kluwer)

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Bacterial Infection
Bladder Infection
Bone infection
Bronchitis
Epiglottitis
Gonococcal Infection, Disseminated
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Kidney Infections
Lyme Disease
Meningitis
Otitis Media
Peritonitis
Pneumonia
Sepsis
Sinusitis
Skin and Structure Infection
Skin Infection
Strep Throat
Surgical Prophylaxis
Tonsillitis/Pharyngitis
Upper Respiratory Tract Infection
Urinary Tract Infection

Where can I get more information?

Your pharmacist can provide more information about cefuroxime.

See also: Ceftin side effects (in more detail)

Vetrazin

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Cyromazine

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Antizol Vet

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Azitromicina Generis

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Anturane

In the US, Anturane (sulfinpyrazone systemic) is a member of the drug class antigout agents and is used to treat Gouty Arthritis.

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Anturane

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Sulfinpyrazone

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QVAR

Generic Name: beclomethasone dipropionate

Dosage Form: aerosol, metered
PRODUCT INFORMATION

QVAR® 40mcg

(beclomethasone dipropionate HFA, 40 mcg)

INHALATION AEROSOL

For Oral Inhalation Only

QVAR® 80mcg

(beclomethasone dipropionate HFA, 80 mcg)

INHALATION AEROSOL

For Oral Inhalation Only

QVAR Description

The active component of QVAR 40 mcg Inhalation Aerosol and QVAR 80 mcg Inhalation Aerosol is beclomethasone dipropionate, USP, an anti-inflammatory corticosteroid having the chemical name 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate. Beclomethasone dipropionate (BDP) is a diester of beclomethasone, a synthetic corticosteroid chemically related to dexamethasone. Beclomethasone differs from dexamethasone in having a chlorine at the 9-alpha carbon in place of a fluorine, and in having a 16 beta-methyl group instead of a 16 alpha-methyl group. Beclomethasone dipropionate is a white to creamy white, odorless powder with a molecular formula of C28H37ClO7 and a molecular weight of 521.1. Its chemical structure is:

QVAR is a pressurized, metered-dose aerosol intended for oral inhalation only. Each unit contains a solution of beclomethasone dipropionate in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. QVAR 40 mcg delivers 40 mcg of beclomethasone dipropionate from the actuator and 50 mcg from the valve. QVAR 80 mcg delivers 80 mcg of beclomethasone dipropionate from the actuator and 100 mcg from the valve. Both products deliver 50 microliters (59 milligrams) of solution formulation from the valve with each actuation. The 40 mcg and the 80 mcg canisters provide either 100 inhalations or 120 inhalations. QVAR should be "primed" or actuated twice prior to taking the first dose from a new canister, or when the inhaler has not been used for more than ten days. Avoid spraying in the eyes or face while priming QVAR. This product does not contain chlorofluorocarbons (CFCs).

QVAR - Clinical Pharmacology

Airway inflammation is known to be an important component in the pathogenesis of asthma. Inflammation occurs in both large and small airways. Corticosteroids have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids such as beclomethasone dipropionate contribute to their efficacy in asthma.

Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP). Beclomethasone 17 monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical significance of these findings is unknown.

Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of QVAR.

Pharmacokinetics

Beclomethasone dipropionate (BDP) undergoes rapid and extensive conversion to beclomethasone-17-monopropionate (17-BMP) during absorption. The pharmacokinetics of 17-BMP has been studied in asthmatics given single doses.

Absorption

The mean peak plasma concentration (Cmax) of BDP was 88 pg/ml at 0.5 hour after inhalation of 320 mcg using QVAR (four actuations of the 80 mcg/actuation strength). The mean peak plasma concentration of the major and most active metabolite, 17-BMP, was 1419 pg/ml at 0.7 hour after inhalation of 320 mcg of QVAR. When the same nominal dose is provided by the two QVAR strengths (40 and 80 mcg/actuation), equivalent systemic pharmacokinetics can be expected. The Cmax of 17-BMP increased dose proportionally in the dose range of 80 and 320 mcg.

Metabolism

Three major metabolites are formed via cytochrome P450 3A catalyzed biotransformation - beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP) and beclomethasone (BOH). Lung slices metabolize BDP rapidly to 17-BMP and more slowly to BOH. 17-BMP is the most active metabolite.

Distribution

The in vitro protein binding for 17-BMP was reported to be 94-96% over the concentration range of 1000 to 5000 pg/mL. Protein binding was constant over the concentration range evaluated. There is no evidence of tissue storage of BDP or its metabolites.

Elimination

The major route of elimination of inhaled BDP appears to be via hydrolysis. More than 90% of inhaled BDP is found as 17-BMP in the systemic circulation. The mean elimination half-life of 17-BMP is 2.8 hours. Irrespective of the route of administration (injection, oral or inhalation), BDP and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine.

Special Populations

Formal pharmacokinetic studies using QVAR were not conducted in any special populations.

Pediatrics

The pharmacokinetics of 17-BMP, including dose and strength proportionalities, is similar in children and adults, although the exposure is highly variable. In 17 children (mean age 10 years), the Cmax of 17-BMP was 787 pg/ml at 0.6 hour after inhalation of 160 mcg (four actuations of the 40 mcg/actuation strength of HFA beclomethasone dipropionate). The systemic exposure to 17-BMP from 160 mcg of HFA-BDP administered without a spacer was comparable to the systemic exposure to 17-BMP from 336 mcg CFC-BDP administered with a large volume spacer in 14 children (mean age 12 years). This implies that approximately twice the systemic exposure to 17-BMP would be expected for comparable mg doses of HFA-BDP without a spacer and CFC-BDP with a large volume spacer.

Pharmacodynamics

Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The effects of QVAR on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 40 corticosteroid naive patients. QVAR, at doses of 80, 160 or 320 mcg twice daily was compared with placebo and 336 mcg twice daily of beclomethasone dipropionate in a CFC propellant based formulation (CFC-BDP). Active treatment groups showed an expected dose-related reduction in 24-hour urinary free cortisol (a sensitive marker of adrenal production of cortisol). Patients treated with the highest recommended dose of QVAR (320 mcg twice daily) had a 37.3% reduction in 24-hour urinary free cortisol compared to a reduction of 47.3% produced by treatment with 336 mcg twice daily of CFC-BDP. There was a 12.2% reduction in 24 hour urinary free cortisol seen in the group of patients that received 80 mcg twice daily of QVAR and a 24.6% reduction in the group of patients that received 160 mcg twice daily. An open label study of 354 asthma patients given QVAR at recommended doses for one year assessed the effect of QVAR treatment on the HPA axis (as measured by both morning and stimulated plasma cortisol). Less than 1% of patients treated for one year with QVAR had an abnormal response (peak less than 18 mcg/dL) to short-cosyntropin test.

Clinical Trials

Blinded, randomized, parallel, placebo-controlled and active-controlled clinical studies were conducted in 940 adult asthma patients to assess the efficacy and safety of QVAR in the treatment of asthma. Fixed doses ranging from 40 mcg to 160 mcg twice daily were compared to placebo, and doses ranging from 40 mcg to 320 mcg twice daily were compared with doses of 42 mcg to 336 mcg twice daily of an active CFC-BDP comparator. These studies provided information about appropriate dosing through a range of asthma severity. A blinded, randomized, parallel, placebo-controlled study was conducted in 353 pediatric patients (age 5-12 years) to assess the efficacy and safety of HFA beclomethasone dipropionate in the treatment of asthma. Fixed doses of 40 mcg and 80 mcg twice daily were compared with placebo in this study. In these adult and pediatric efficacy trials, at the doses studied, measures of pulmonary function [forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow (AM PEF)] and asthma symptoms were significantly improved with QVAR treatment when compared to placebo.

In controlled clinical trials with adult patients not adequately controlled with beta-agonist alone, QVAR was effective at improving asthma control at doses as low as 40 mcg twice daily (80 mcg/day). Comparable asthma control was achieved at lower daily doses of QVAR than with CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP generally resulted in increased improvement in FEV1. In this trial the improvement in FEV1 across doses was greater for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR.

Patients Not Previously Receiving Corticosteroid Therapy

In a 6 week clinical trial, 270 steroid naive patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 40 mcg twice daily of QVAR, 80 mcg twice daily of QVAR, or placebo. Both doses of QVAR were effective in improving asthma control with significantly greater improvements in FEV1, AM PEF, and asthma symptoms than with placebo. Shown below is the change from baseline in AM PEF during this trial.

A 6-Week Clinical Trial in Patients with Mild to Moderate Asthma Not on

Corticosteroid Therapy Prior to Study Entry:

Mean Change in AM PEF

In a 6-week clinical trial, 256 patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 160 mcg twice daily of QVAR (delivered as either 40 mcg/actuation or 80 mcg/actuation) or placebo. Treatment with QVAR significantly improved asthma control, as assessed by FEV1, AM PEF, and asthma symptoms, when compared to treatment with placebo. Comparable improvement in AM PEF was seen for patients receiving 160 mcg twice daily QVAR from the 40 mcg and 80 mcg strength products.

Patients Responsive to a Short Course of Oral Corticosteroids

In another clinical trial, 347 patients with symptomatic asthma, being treated with as-needed inhaled beta-agonist bronchodilators and, in some cases, inhaled corticosteroids, were given a 7-12 day course of oral corticosteroids and then randomized to receive either 320 mcg daily of QVAR, 672 mcg of CFC-BDP, or placebo. Patients treated with either QVAR or CFC-BDP had significantly better asthma control, as assessed by AM PEF, FEV1 and asthma symptoms, and fewer study withdrawals due to asthma symptoms, than those treated with placebo over 12 weeks of treatment. A daily dose of 320 mcg QVAR administered in divided doses provided comparable control of AM PEF and FEV1 as 672 mcg of CFC-BDP. Shown below are the mean AM PEF results from this trial.

A 12-Week Clinical Trial in Moderate Symptomatic Patients with

Asthma Responding to Oral Corticosteroid Therapy: Mean AM PEF by Study Week

Patients Previously on Inhaled Corticosteroids

In a 6-week clinical trial, 323 patients, who exhibited a deterioration in asthma control during an inhaled corticosteroid washout period, were randomized to daily treatment with either 40, 160, or 320 mcg twice daily QVAR or 42, 168, or 336 mcg twice daily CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP resulted in increased improvement in FEV1, FEF25-75% (forced expiratory flow over 25-75% of the vital capacity), and asthma symptoms. Shown below is the change from baseline in FEV1 as percent predicted after 6 weeks of treatment.

A 6-Week Dose Response Clinical Trial in Patients with Inhaled Corticosteroid Dependent Asthma:

Mean Change in FEV1 as Percent of Predicted

Patients Previously Maintained on Oral Corticosteroids

Clinical experience has shown that some patients with asthma who require oral corticosteroid therapy for control of symptoms can be partially or completely withdrawn from oral corticosteroids if therapy with beclomethasone dipropionate aerosol is substituted. Inhaled corticosteroids may not be effective for all patients with asthma or at all stages of the disease in a given patient.

Pediatric Experience

In one 12-week clinical trial, pediatric patients (age 5-12 years) with symptomatic asthma (N=353) being treated with as-needed beta-agonist bronchodilators were randomized to receive either 40 mcg or 80 mcg twice daily of HFA beclomethasone dipropionate or placebo. Both doses were effective in improving asthma control with significantly greater improvements in FEV1 (9% and 10% predicted change from baseline at week 12 in FEV1 percent predicted, respectively) than with placebo (4% predicted change).

Indications and Usage for QVAR

QVAR is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. QVAR is also indicated for asthma patients who require systemic corticosteroid administration, where adding QVAR may reduce or eliminate the need for the systemic corticosteroids.

Beclomethasone dipropionate is NOT indicated for the relief of acute bronchospasm.

Contraindications

QVAR is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

Warnings

Particular care is needed in patients who are transferred from systemically active corticosteroids to QVAR because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections (particularly gastroenteritis) or other conditions with severe electrolyte loss. Although QVAR may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid that is necessary for coping with these emergencies.

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack.

Transfer of patients from systemic steroid therapy to QVAR may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection. Nor is the contribution of the underlying disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

QVAR is not a bronchodilator and is not indicated for rapid relief of bronchospasm.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with QVAR, it should be treated immediately with a short acting inhaled bronchodilator. Treatment with QVAR should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma, which are not responsive to bronchodilators, occur during the course of treatment with QVAR. During such episodes, patients may require therapy with oral corticosteroids.

Precautions

General

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. Although suppression of HPA function below the clinical normal range did not occur with doses of QVAR up to and including 640 mcg/day, a dose dependent reduction of adrenal cortisol production was observed. Since inhaled beclomethasone dipropionate is absorbed into the circulation and can be systemically active, HPA axis suppression by QVAR could occur when recommended doses are exceeded or in particularly sensitive individuals. Since individual sensitivity to effects on cortisol production exist, physicians should consider this information when prescribing QVAR. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effect. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects, such as hypercorticism and adrenal suppression, may appear in a small number of patients, particularly at higher doses. If such changes occur, QVAR should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.

A 12 month randomized controlled clinical trial evaluated the effects of HFA beclomethasone dipropionate without spacer versus CFC beclomethasone dipropionate with large volume spacer on growth in children age 5-11. A total of 520 patients were enrolled, of whom 394 received HFA-BDP (100 – 400 mcg/day ex-valve) and 126 received CFC-BDP (200 – 800 mcg/day ex-valve). Similar control of asthma was noted in each treatment arm. When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-BDP was approximately 0.5 cm/year less than that noted with children treated with CFC-BDP via large volume spacer.

A reduction in growth velocity in growing children may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of all pediatric patients taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression.

The long-term and systemic effects of QVAR in humans are still not fully known. In particular, the effects resulting from chronic use of the agent on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids.

Information for Patients

Patients being treated with QVAR should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed to these diseases, medical advice should be sought without delay.

Patients should use QVAR at regular intervals as directed. Results of clinical trials indicated significant improvements may occur within the first 24 hours of treatment in some patients; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks, or longer. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.

Patients should be advised that QVAR is not intended for use in the treatment of acute asthma. The patient should be instructed to contact their physician immediately if there is any deterioration of their asthma.

Patients should be instructed on the proper use of their inhaler. Patients may wish to rinse their mouth after QVAR use. The patient should also be advised that QVAR may have a different taste and inhalation sensation than that of an inhaler containing CFC propellant.

QVAR use should not be stopped abruptly. The patient should contact their physician immediately if use of QVAR is discontinued.

For the proper use of QVAR, the patient should read and carefully follow the accompanying Patient's Instructions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day. There was no evidence of carcinogenicity in this study at the highest dose, which is approximately 30 and 55 times the maximum recommended daily inhalation dose in adults and children, respectively, on a mg/m2 basis.

Beclomethasone dipropionate did not induce gene mutation in the bacterial cells or mammalian Chinese Hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg/day (approximately 200 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). Impairment of fertility, as evidence by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 20 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the Inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Like other corticosteroids, parenteral (subcutaneous) beclomethasone dipropionate was teratogenic and embryocidal in the mouse and rabbit when given at a dose of 0.1 mg/kg/day in mice or at a dose of 0.025 mg/kg/day in rabbits. These doses in mice and rabbits were approximately one-half the maximum recommended daily inhalation dose in adults on a mg/m2 basis. No teratogenicity or embryocidal effects were seen in rats when exposed to an inhalation dose of 15 mg/kg/day (approximately 190 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). There are no adequate and well controlled studies in pregnant women. Beclomethasone dipropionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects

Findings of drug-related adrenal toxicity in fetuses following administration of beclomethasone dipropionate to rats suggest that infants born of mothers receiving substantial doses of QVAR during pregnancy should be observed for adrenal suppression.

Nursing Mothers

Corticosteroids are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from QVAR, 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.

Pediatric Use

Eight-hundred and thirty-four children between the ages of 5 and 12 were treated with HFA beclomethasone dipropionate (HFA BDP) in clinical trials. The safety and effectiveness of QVAR in children below 5 years of age have not been established.

Use of QVAR with a spacer device in children less than 5 years of age is not recommended. In vitro dose characterization studies were performed with QVAR 40 mcg/actuation with the Optichamber and AeroChamber Plus® spacer utilizing inspiratory flows representative of children under 5 years old. These studies indicated that the amount of medication delivered through the spacing device decreased rapidly with increasing wait times of 5 to 10 seconds as shown in Table 1. If QVAR is used with a spacer device, it is important to inhale immediately.

Based on the average inspiratory flow rates generated by children 6 months to 5 years old, the projected daily dose derived from QVAR 40 mcg at one puff per day at various wait times is depicted in the table below:

TABLE 1
	Wait time, seconds	Mean medication delivery through AeroChamber, mcg/actuation *	Body Weight 50th percentile, kg †	Medication delivered per dose, mcg/kg ‡,§
* Summary Report; Pediatric Dose Characterization of QVAR with Spacer; 3M Pharmaceutical Development, July 21, 2004. † CDC Growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). ‡ Includes an estimated 20% loss in the masks § QVAR 40mcg in an average adult without using a spacer delivers approximately 0.4 mcg/kg, or bid, 0.8 mcg/kg/day.
Age 6 months, Flow rate 4.8 L/min	0	11.5	7.6	1.2
Age 2 years, Flow rate 8.2 L/min	0	14.1	13.5	0.83
Age 2 years, Flow rate 8.2 L/min	5	5.4	13.5	0.32
Age 2 years, Flow rate 8.2 L/min	10	3.9	13.5	0.23
Age 5 years, Flow rate 11.0 L/min	0	17.5	18	0.78

Oral inhaled corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS, General).

Geriatric Use

Clinical studies of QVAR 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.

Adverse Reactions

The following reporting rates of common adverse experiences are based upon four clinical trials in which 1196 Patients (671 female and 525 male adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with QVAR (doses of 40, 80, 160, or 320 mcg twice daily) or CFC-BDP (doses of 42, 168, or 336 mcg twice daily) or placebo. The table below includes all events reported by patients taking QVAR (whether considered drug related or not) that occurred at a rate over 3% for either QVAR or CFC-BDP. In considering these data, difference in average duration of exposure and clinical trial design should be taken into account.

Adverse Events Reported by at Least 3% of the Patients for Either QVAR or CFC-BDP by Treatment and Daily Dose
Adverse Events		QVAR				CFC-BDP
Adverse Events	Placebo (N=289) %	Total (N=624) %	80-160 mcg (N=233) %	320 mcg (N=335) %	640 mcg (N=56) %	Total (N=283) %	84 mcg (N=59) %	336 mcg (N=55) %	672 mcg (N=169) %
HEADACHE	9	12	15	8	25	15	14	11	17
PHARYNGITIS	4	8	6	5	27	10	12	9	10
UPPER RESP TRACT INFECTION	11	9	7	11	5	12	3	9	17
RHINITIS	9	6	8	3	7	11	15	9	10
INCREASED ASTHMA SYMPTOMS	18	3	2	4	0	8	14	5	7
ORAL SYMPTOMS INHALATION ROUTE	2	3	3	3	2	6	7	5	5
SINUSITIS	2	3	3	3	0	4	7	2	4
PAIN	<1	2	1	2	5	3	3	5	2
BACK PAIN	1	1	2	<1	4	4	2	4	4
NAUSEA	0	1	<1	1	2	3	5	5	1
DYSPHONIA	2	<1	1	0	4	4	0	0	6

Other adverse events that occurred in these clinical trials using QVAR with an incidence of 1% to 3% and which occurred at a greater incidence than placebo were: dysphonia, dysmenorrhea and coughing.

No patients treated with QVAR in the clinical development program developed symptomatic oropharyngeal candidiasis.

If such an infection develops, treatment with appropriate antifungal therapy or discontinuance of treatment with QVAR may be required.

Pediatric Studies

In two 12-week placebo controlled studies in steroid naive pediatric patients 5 to 12 years of age, no clinically relevant differences were found in the pattern, severity, or frequency of adverse events compared with those reported in adults, with the exception of conditions which are more prevalent in a pediatric population generally.

Adverse Event Reports from Other Sources

Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm, have been reported following the oral and intranasal inhalation of beclomethasone dipropionate.

Overdosage

There were no deaths over 15 days following the oral administration of a single dose of 3000 mg/kg in mice, 2000 mg/kg in rats, and 1000 mg/kg in rabbits. The doses in mice, rats, and rabbits were 19,000, 25,000, and 25,000 times, respectively, the maximum recommended daily inhalation in adults or 36,000, 48,000, and 48,000 times, respectively the maximum recommended daily inhalation dose in children on a mg/m2 basis.

QVAR Dosage and Administration

Patients should prime QVAR by actuating into the air twice before using for the first time or if QVAR has not been used for over ten days. Avoid spraying in the eyes or face when priming QVAR. QVAR is a solution aerosol, which does not require shaking. Consistent dose delivery is achieved, whether using the 40 or 80 mcg strengths, due to proportionality of the two products (i.e., two actuations of 40 mcg strength should provide a dose comparable to one actuation of the 80 mcg strength).

QVAR should be administered by the oral inhaled route in patients 5 years of age and older. Use of QVAR with a spacer device in children less than 5 years of age is not recommended (see PRECAUTIONS, Pediatric Use). The onset and degree of symptom relief will vary in individual patients. Improvement in asthma symptoms should be expected within the first or second week of starting treatment, but maximum benefit should not be expected until 3-4 weeks of therapy. For patients who do not respond adequately to the starting dose after 3-4 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of QVAR when administered in excess of recommended doses has not been established.

Table 2: Recommended Dosing for Adults and Adolescents
Patient's Previous Therapy	Recommended Starting Dose	Highest Recommended Dose
Bronchodilators Alone	40 to 80 mcg twice daily	320 mcg twice daily
Inhaled Corticosteroids	40 to 160 mcg twice daily	320 mcg twice daily

Table 3: Recommended Dosing for Children 5 to 11 Years
Patient's Previous Therapy	Recommended Starting Dose	Highest Recommended Dose
Bronchodilators Alone	40 mcg twice daily	80 mcg twice daily
Inhaled Corticosteroids	40 mcg twice daily	80 mcg twice daily

As with any inhaled corticosteroid, physicians are advised to titrate the dose of QVAR downward over time to the lowest level that maintains proper asthma control. This is particularly important in children since a controlled study has shown that QVAR has the potential to affect growth in children. Patients should be instructed on the proper use of their inhaler.

Patients Not Receiving Systemic Corticosteroids

Patients who require maintenance therapy of their asthma may benefit from treatment with QVAR at the doses recommended above. In patients who respond to QVAR, improvement in pulmonary function is usually apparent within 1 to 4 weeks after the start of therapy. Once the desired effect is achieved, consideration should be given to tapering to the lowest effective dose.

Patients Maintained on Systemic Corticosteroids

QVAR may be effective in the management of asthmatics maintained on systemic corticosteroids and may permit replacement or significant reduction in the dosage of systemic corticosteroids.

The patient's asthma should be reasonably stable before treatment with QVAR is started. Initially, QVAR should be used concurrently with the patient's usual maintenance dose of systemic corticosteroids. After approximately one week, gradual withdrawal of the systemic corticosteroids is started by reducing the daily or alternate daily dose. Reductions may be made after an interval of one or two weeks, depending on the response of the patient. A slow rate of withdrawal is strongly recommended. Generally these decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, e.g. joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with the inhaler but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly.

During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.

DIRECTIONS FOR USE

Illustrated Patient's Instructions for proper use accompany each package of QVAR.

How is QVAR Supplied

QVAR is supplied in two strengths:

: QVAR 40 mcg is supplied either in a 7.3 g canister containing 100 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-175-40 or in an 8.7 g canister containing 120 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-202-40
: QVAR 80 mcg is supplied either in a 7.3 g canister containing 100 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-177-80 or in an 8.7 g canister containing 120 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-204-80

The correct amount of medication in each inhalation cannot be assured after 100 actuations from the 7.3 g canister or 120 actuations from the 8.7 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used.

Store QVAR Inhalation Aerosol when not being used, so that the product rests on the concave end of the canister with the plastic actuator on top.

Store at 25°C (77°F).

Excursions between 15° and 30°C (59° and 86°F) are permitted (see USP). For optimal results, the canister should be at room temperature when used. QVAR Inhalation Aerosol canister should only be used with the QVAR Inhalation Aerosol actuator and the actuator should not be used with any other inhalation drug product.

CONTENTS UNDER PRESSURE

Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw container into fire or incinerator.

Keep out of reach of children.

Rx only

U.S. Patent Nos. 5605674, 5683677, 5695743, 5776432

Mktd by:

Teva Respiratory, LLC– Horsham, PA 19044

Developed and Manufactured by:

3M Drug Delivery Systems

Northridge, CA 91324

3M Health Care, Ltd.

Loughborough, UK

September, 2010

© 2010 Teva Respiratory, LLC

639300

QVAR® is a registered trademark of IVAX LLC, a member of the TEVA Group.

Rev. 09/10

OptiChamber is a registered trademark of Respironics Healthscan, Inc. and AeroChamber Plus is a registered trademark of Trudell Medical International Trudell Partnership Holdings Limited and Packard Medical Supply Centre Ltd.

PATIENT'S INSTRUCTIONS

QVAR®

(beclomethasone dipropionate HFA)

INHALATION AEROSOL

Attention Pharmacist: Detach "PATIENT'S INSTRUCTIONS for Use" from package insert and dispense with the product.

PATIENT'S INSTRUCTIONS

It is important that you read these instructions before using QVAR.

Correct and regular use of the inhaler will prevent