Out of scope - Out of scope for RxNorm and will not receive RxNorm normal forms. Out of scope information includes radiopharmaceuticals, contrast media, herbals, homeopathics, and food. Drug names that are ambiguous or not compatible with the RxNorm system, such as multivitamins with more than 4,000 characters in their names, are also out of scope.
STIPTIK (Ferric Subsulfate) Solution [Island Kinetics, Inc. D.B.A. CoValence Laboratories]vendredi 30 juin 2017
CITALOPRAM Tablet [Cipla USA Inc.]
The premarketing development program for citalopram included citalopram exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4,422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1,370 patient-exposure years. There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies. The conditions and duration of treatment with citalopram varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and short-term and long-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials
Adverse Events Associated with Discontinuation of Treatment
Among 1,063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of citalopram-treated patients at a rate at least twice that of placebo) are shown in TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.
Adverse Events Occurring at an Incidence of 2% or More Among Citalopram-Treated Patients
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1,063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with citalopram and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients.
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
The only commonly observed adverse event that occurred in citalopram patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see TABLE 3).
Dose Dependency of Adverse Events
The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10 mg, 20 mg, 40 mg, or 60 mg. Jonckheere's trend test revealed a positive dose response (p<0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.
The table below displays the incidence of sexual side effects reported by at least 2% of patients taking citalopram in a pool of placebo-controlled clinical trials in patients with depression.
In female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1.3% (n= 638 females) and 1.1% (n= 252 females), respectively.
There are no adequately designed studies examining sexual dysfunction with citalopram treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital Sign Changes
Citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes.
Weight Changes
Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.
Laboratory Changes
Citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment.
ECG Changes
In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes).
Electrocardiograms from citalopram (N=802) and placebo (N=241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF >60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-dose QTcF >500 msec compared to 0.5% of the patients in the citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.
Other Events Observed During the Premarketing Evaluation of Citalopram HBr
Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by patients treated with citalopram at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4,422 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
Cardiovascular -Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. Rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.
Central and Peripheral Nervous System Disorders -Frequent: paresthesia, migraine. Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination, hyperesthesia, ptosis, stupor.
Endocrine Disorders -Rare: hypothyroidism, goiter, gynecomastia.
Gastrointestinal Disorders -Frequent: saliva increased, flatulence. Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. Rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.
General -Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. Rare: hayfever.
Hemic and Lymphatic Disorders -Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.
Metabolic and Nutritional Disorders -Frequent: decreased weight, increased weight. Infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.
Musculoskeletal System Disorders -Infrequent: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis.
Psychiatric Disorders -Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. Infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. Rare: catatonic reaction, melancholia.
Reproductive Disorders/Female* -Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.
*% based on female subjects only: 2,955
Respiratory System Disorders -Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.
Skin and Appendages Disorders -Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.
Special Senses -Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.
Urinary System Disorders -Frequent: polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.
Other Events Observed During the Postmarketing Evaluation of Citalopram HBr
It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, angle closure glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.
Close CITALOPRAM Tablet [Cipla USA Inc.]LINZESS (Linaclotide) Capsule, Gelatin Coated [Allergan, Inc]
14.1 Irritable Bowel Syndrome with Constipation (IBS-C)
The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 to 87 years), 90% female, 77% white, 19% black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy. All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria:
- a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale
- less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and
- less than or equal to 5 SBMs per week.
The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation.
Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.
The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.
For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.
The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively. In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo.
In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods. For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week. Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials.
In each trial, in addition to improvements in abdominal pain and CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the Bristol Stool Form Scale (BSFS)], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool].
During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg. In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and a decrease in abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period.
14.2 Chronic Idiopathic Constipation (CIC)
The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 to 85 years), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:
- Straining during greater than 25% of bowel movements
- Lumpy or hard stools during greater than 25% of bowel movements
- Sensation of incomplete evacuation during greater than 25% of bowel movements
Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.
The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation.
The efficacy of LINZESS was assessed using a responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.
A CSBM responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 5. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 5.
In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo.
CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs.
On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).
In each trial, in addition to improvements in CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in each of the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the BSFS], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool].
During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period.
A 72 mcg dose of LINZESS was established in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients (Trial 5). A total of 1223 patients [overall mean age of 46 years (range 18 to 90 years), 77% female, 71% white, 24% black, 43% Hispanic] received treatment with LINZESS 72 mcg or placebo once daily and were evaluated for efficacy. All patients met modified Rome III criteria for functional constipation. Trial 5 was identical to Trials 3 and 4 through the first 12 weeks. The efficacy of the 72 mcg dose was assessed using a responder analysis where a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period, which was the same as the one defined in Trials 3 and 4. The response rates for the CSBM responder endpoint were 13% for LINZESS 72 mcg and 5% for placebo. The difference between LINZESS 72 mcg and placebo was 9% (95% CI: 4.8%, 12.5%).
A separate analysis was performed using an alternate CSBM responder definition. In this analysis a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period and at least 3 of the last 4 weeks of the treatment period. The response rates for the alternate CSBM responder endpoint were 12% for LINZESS 72 mcg and 5% for placebo. The difference between LINZESS 72 mcg and placebo was 8% (95% CI: 3.9%, 11.5%).
jeudi 29 juin 2017
FELBAMATE Suspension [Taro Pharmaceuticals U.S.A., Inc.]
To report SUSPECTED ADVERSE REACTIONS, contact Taro at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The most common adverse reactions seen in association with felbamate in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache.
The most common adverse reactions seen in association with felbamate in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache.
The most common adverse reactions seen in association with felbamate in children during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence.
The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%), dermatological (1.4%), psychological (1.1%), and whole body (1%). In adults, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency were: anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was rash (1.1%).
Incidence in Clinical Trials
The prescriber should be aware that the figures cited in the following table cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different investigators, treatments, and uses including the use of felbamate as adjunctive therapy where the incidence of adverse events may be higher due to drug interactions. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
Adults
Incidence in Controlled Clinical Trials--Monotherapy Studies in Adults
The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58 adult patients who received felbamate monotherapy at dosages of 3600 mg/day in double-blind controlled trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary terminology.
Incidence in Controlled Add-On Clinical Studies in Adults
Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients who received felbamate adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology.
Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions. Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or with adjustment of the dosage of other antiepileptic drugs.
Children
Incidence in a Controlled Add-On Trial in Children with Lennox-Gastaut Syndrome
Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who received felbamate up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology.
Other Events Observed in Association with the Administration of Felbamate
In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that occurred in a total of 977 adults and 357 children exposed to felbamate and that are reasonably associated with its use are presented. They are listed in order of decreasing frequency. Because the reports cite events observed in open-label and uncontrolled studies, the role of felbamate in their causation cannot be reliably determined.
Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients.
Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=1334) exposed to felbamate.
Body as a Whole: Frequent: Weight increase, asthenia, malaise, influenza-like symptoms; Rare: anaphylactoid reaction, chest pain substernal.
Cardiovascular: Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia.
Central Nervous System: Frequent: Agitation, psychological disturbance, aggressive reaction: Infrequent: hallucination, euphoria, suicide attempt, migraine.
Digestive: Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated.
Hematologic: Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia, granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis.
Metabolic/Nutritional: Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase increased, hypophosphatemia; Rare: creatinine phosphokinase increased.
Musculoskeletal: Infrequent: Dystonia.
Dermatological: Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous membrane swelling, Stevens-Johnson Syndrome.
Special Senses: Rare: Photosensitivity allergic reaction.
Postmarketing Adverse Event Reports
Voluntary reports of adverse events in patients taking felbamate (usually in conjunction with other drugs) have been received since market introduction and may have no causal relationship with the drug(s). These include the following by body system:
Body as a Whole: neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors, hyperpyrexia.
Cardiovascular: atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure, hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia, bradycardia, Henoch-Schönlein purpura (vasculitis).
Central & Peripheral Nervous System: delusion, paralysis, mononeuritis, cerebrovascular disorder, cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis, extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory depression, apathy, concentration impaired.
Dermatological: abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic epidermal necrolysis.
Digestive: (Refer to WARNINGS) hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia, pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer, gastric dilatation, gastroesophageal reflux.
Fetal Disorders: fetal death, microcephaly, genital malformation, anencephaly, encephalocele.
Hematologic: (Refer to WARNINGS) increased and decreased prothrombin time, anemia, hypochromic anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume (mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma, including T-cell and B-cell lymphoproliferative disorders.
Metabolic/Nutritional: hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration, hyperglycemia, hypocalcemia.
Musculoskeletal: arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis.
Respiratory: dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory insufficiency, pulmonary hemorrhage, asthma.
Special Senses: hemianopsia, decreased hearing, conjunctivitis.
Urogenital: menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention, nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder.
LAMIVUDINE AND ZIDOVUDINE Tablet, Film Coated [PD-Rx Pharmaceuticals, Inc.]
12.1 Mechanism of Action
Lamivudine and zidovudine tablets are an antiviral agent [ see Clinical Pharmacology ( 12.4) ].
12.3 Pharmacokinetics
Pharmacokinetics in Adults: Lamivudine and zidovudine tablets: One lamivudine and zidovudine tablet was bioequivalent to 1 EPIVIR ® (lamivudine) Tablet (150 mg) plus 1 RETROVIR ® (zidovudine) Tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).
Lamivudine: The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 3. Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).
Zidovudine: The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 3. Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3 fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine AUC.
Effect of Food on Absorption of Lamivudine and Zidovudine Tablets: Lamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablets with food was similar when compared to fasting healthy subjects (n = 24).
Special Populations:
Pregnancy: See Use in Specific Populations ( 8.1) .
Lamivudine and Zidovudine Tablets: No data are available.
Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult population, a potential for interaction has been identified.
Nursing Mothers: See Use in Specific Populations ( 8.3) .
Pediatric Patients: Lamivudine and zidovudine tablets should not be administered to pediatric patients weighing less than 30 kg.
Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine AUC ∞ or lamivudine AUC ∞ normalized for body weight.
Race: Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.
Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.
Drug Interactions: See Drug Interactions ( 7) .
No drug interaction studies have been conducted using lamivudine and zidovudine tablets. However, Table 4 presents drug interaction information for the individual components of lamivudine and zidovudine tablets.
Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [ see Warnings and Precautions ( 5.5) ].
12.4 Microbiology
Mechanism of Action: Lamivudine: Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of cellular DNA polymerases α, ß, and γ.
Zidovudine: Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity: Lamivudine Plus Zidovudine: In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.
Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC 50 values (50% effective concentrations) were in the range of 0.003 to 15 μM (1 μM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC 50 values of 0.429 μM (range: 0.200 to 2.007 μM) from Virco (n = 92 baseline samples from COL40263) and 2.35 μM (1.37 to 3.68 μM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC 50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 μM, and against HIV-2 isolates from 0.003 to 0.120 μM in peripheral blood mononuclear cells. Ribavirin (50 μM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells.
Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC 50 and EC 90 values for zidovudine were 0.01 to 0.49 μM (1 μM = 0.27 mcg/mL) and 0.1 to 9 μM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC 50 values of 0.011 μM (range: 0.005 to 0.110 μM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 μM (0.006 to 0.0340 μM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC 50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Resistance: Lamivudine Plus Zidovudine Administered As Separate Formulations: In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of amino acid substitutions conferring resistance to zidovudine.
HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.
Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from patients treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated patients showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I).
Zidovudine: HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from patients treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed substitutions in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions.
Cross-Resistance: Cross-resistance has been observed among NRTIs.
Lamivudine Plus Zidovudine: Cross-resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to lamivudine. Cross-resistance to abacavir, didanosine, tenofovir, and zalcitabine has been observed in some patients harboring lamivudine-resistant HIV-1 isolates. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged (see under Zidovudine below).
Lamivudine: See Lamivudine Plus Zidovudine (above).
Zidovudine: In a study of 167 HIV-1-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥ 1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
CANDESARTAN CILEXETIL Tablet [Alembic Pharmaceuticals Inc.]
Advise patient to read FDA-approved patient labeling (Patient Information).
Pregnancy
Advise female patients of childbearing age should be told about the consequences of exposure to candesartan cilexetil tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
Manufactured by:
Alembic Pharmaceuticals Limited
(Formulation Division),
Panelav 389350, Gujarat, India
Manufactured for:
Alembic Pharmaceuticals, Inc.
750 Route 202, Bridgewater, NJ 08807
USA
Revised: 04/2017
Patient Information
Candesartan Cilexetil (kan-de-sar-tan sye-lex-e-til) Tablets
Read the Patient information that comes with candesartan cilexetil tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about candesartan cilexetil tablets, ask your doctor or pharmacist.
What is the most important information I should know about candesartan cilexetil tablets?
Candesartan cilexetil tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking candesartan cilexetil tablets, tell your doctor right away.
What are candesartan cilexetil tablets?
Candesartan cilexetil tablets are a prescription medicine called an angiotensin receptor blocker (ARB).
Candesartan cilexetil tablets are used to:
• treat high blood pressure in adults and children, 1 to 17 years of age
• treat certain types of heart failure in adults, to reduce death and hospitalization for heart damage and heart failure
Heart failure is a condition where the heart does not pump blood as well as it should.
Candesartan cilexetil tablets must not be used in children less than 1 year of age for high blood pressure.
Who should not take candesartan cilexetil tablets?
Do not take candesartan cilexetil tablet if you:
• are allergic to any of the ingredients in candesartan cilexetil tablets. See the end of this leaflet for a complete list of ingredients in candesartan cilexetil tablets.
• are diabetic and taking aliskiren.
What should I tell my doctor before taking candesartan cilexetil tablets?
Before you take candesartan cilexetil tablets, tell your doctor if you:
• have heart problems
• have liver problems
• have kidney problems
• currently have vomiting or diarrhea
• are scheduled for surgery or anesthesia. Low blood pressure can happen in people who take candesartan cilexetil tablets and have major surgery and anesthesia.
• have any other medical conditions
• are pregnant or planning to become pregnant. See “What is the most important information I should know about candesartan cilexetil tablets?”
• are breast-feeding or plan to breast-feed. It is not known if candesartan cilexetil passes into your breast milk. You and your doctor should decide if you will take candesartan cilexetil tablets or breast-feed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Candesartan cilexetil tablets and other medicines may affect each other causing serious side effects. Candesartan cilexetil tablets may affect the way other medicines work, and other medicines may affect how candesartan cilexetil tablets works.
Especially tell your doctor if you take:
• lithium carbonate (Lithobid) or lithium citrate, medicines used in some types of depression
• other medicines for high blood pressure, especially water pills (diuretics)
• potassium supplements
• salt substitutes
• non-steroidal anti-inflammatory drugs (NSAIDs)
Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together.
How should I take candesartan cilexetil tablets?
• Take candesartan cilexetil tablets exactly as prescribed by your doctor.
• Do not change your dose or stop candesartan cilexetil tablets without talking to your doctor, even if you are feeling well.
• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare candesartan cilexetil as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will change the dose as needed. Shake the bottle of suspension well before each dose.
• Candesartan cilexetil tablets are taken by mouth with or without food.
• If you miss a dose of candesartan cilexetil tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose on time. Do not take 2 doses at one time. If you are not sure about your dosing call your doctor or pharmacist.
• If you take more candesartan cilexetil tablets than prescribed, call your doctor, local poison control center, or go to the nearest emergency room.
What should I avoid while taking candesartan cilexetil tablets?
Candesartan cilexetil tablets can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how candesartan cilexetil tablets affects you.
What are the possible side effects of candesartan cilexetil tablets?
Candesartan cilexetil tablets may cause serious side effects, including:
• Injury or death to your unborn baby. See “What is the most important information I should know about candesartan cilexetil tablets?
• Low blood pressure (hypotension). Low blood pressure is most likely to happen if you:
o take water pills (diuretics)
o are on a low salt diet
o get dialysis treatments
o are dehydrated (decreased body fluids) due to vomiting and diarrhea
o have heart problems
If you feel dizzy or faint lie down and call your doctor right away.
Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking candesartan cilexetil tablets?”
• Worsening kidney problems. Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this.
• Increased potassium in your blood. Your doctor may do a blood test to check your potassium levels as needed.
• Symptoms of allergic reaction. Call your doctor right away if you have any of these symptoms of an allergic reaction:
o swelling of your face, lips, tongue or throat
o rash
o hives and itching
The most common side effects of candesartan cilexetil tablets are:
• back pain
• dizziness
• cold or flu symptoms (upper respiratory tract infection)
• sore throat (pharyngitis)
• nasal congestion and stuffiness (rhinitis)
Tell your doctor or pharmacist about any side effect that bothers you or that does not go away.
These are not all the side effects of candesartan cilexetil tablets. Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.
How should I store candesartan cilexetil tablets?
• Do not keep medicine that is out of date or that you no longer need.
• Store candesartan cilexetil tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
• Store candesartan cilexetil oral suspension at room temperature below 30°C (86°F).
• Use the oral suspension within 30 days after first opening the bottle. Do not use after the expiration date stated on the bottle.
• Do not freeze.
• Keep the container of candesartan cilexetil tablets closed tightly.
Keep candesartan cilexetil tablets and all medicine out of the reach of children.
General information about candesartan cilexetil tablets.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use candesartan cilexetil tablets for a condition for which it was not prescribed. Do not give candesartan cilexetil tablets to other people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important information about candesartan cilexetil tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about candesartan cilexetil tablets that is written for health professionals.
For more information, call Alembic Pharmaceuticals Limited at 1-866 210 9797.
What are the ingredients in candesartan cilexetil tablets?
Active ingredient: candesartan cilexetil.
Inactive ingredients in candesartan cilexetil tablets are: mannitol, pullulan, carboxymethylcellulose calcium, corn starch, polyethylene glycol, hydroxypropyl cellulose, magnesium stearate and lactose monohydrate. Iron oxide red is added to the 32-mg tablet as a colorant.
In addition to the above, candesartan cilexetil oral suspension also includes the following inactive ingredients: Ora-Plus, Ora Sweet or Ora-Blend.
How do candesartan cilexetil tablets work?
Candesartan cilexetil tablets are a type of medicine called angiotensin receptor blocker, which blocks the effect of the hormone angiotensin II, causing the blood vessels to relax. This helps lower blood pressure. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Ora-Plus®, Ora-Sweet SF®, and Ora-Blend SF® are registered trademarks of Paddock Laboratories, Inc.
Manufactured by:
Alembic Pharmaceuticals Limited
(Formulation Division),
Panelav 389350, Gujarat, India
Manufactured for:
Alembic Pharmaceuticals, Inc.
750 Route 202, Bridgewater, NJ 08807
USA
Revised: 04/2017
Close CANDESARTAN CILEXETIL Tablet [Alembic Pharmaceuticals Inc.]
mercredi 28 juin 2017
BENZTROPINE MESYLATE Tablet [REMEDYREPACK INC.]
Benztropine mesylate tablets should be used when patients are able to take oral medication.
The injection is especially useful for psychotic patients with acute dystonic reactions or other reactions that make oral medication difficult or impossible. It is recommended also when a more rapid response is desired than can be obtained with the tablets.
Because of cumulative action, therapy should be initiated with a low dose which is increased gradually at five or six-day intervals to the smallest amount necessary for optimal relief. Increases should be made in increments of 0.5 mg, to a maximum of 6 mg, or until optimal results are obtained without excessive adverse reactions.
Postencephalitic and Idiopathic Parkinsonism -
The usual daily dose is 1 to 2 mg, with a range of 0.5 to 6 mg orally or parentally.
As with any agent used in parkinsonism, dosage must be individualized according to age and weight, and the type of parkinsonism being treated. Generally, older patients, and thin patients cannot tolerate large doses. Most patients with postencephalitic parkinsonism need fairly large doses and tolerate them well. Patients with a poor mental outlook are usually poor candidates for therapy.
In idiopathic parkinsonism, therapy may be initiated with a single daily dose of 0.5 to 1 mg at bedtime. In some patients, this will be adequate; in others 4 to 6 mg a day may be required.
In postencephalitic parkinsonism, therapy may be initiated in most patients with 2 mg a day in one or more doses. In highly sensitive patients, therapy may be initiated with 0.5 mg at bedtime, and increased as necessary.
Some patients experience greatest relief by taking the entire dose at bedtime; others react more favorably to divided doses, two to four times a day. Frequently, one dose a day is sufficient, and divided doses may be unnecessary or undesirable.
The long duration of action of this drug makes it particularly suitable for bedtime medication when its effects may last throughout the night, enabling patients to turn in bed during the night more easily, and to rise in the morning.
When benztropine mesylate is started, do not terminate therapy with other antiparkinsonian agents abruptly. If the other agents are to be reduced or discontinued, it must be done gradually. Many patients obtain greatest relief with combination therapy.
Benztropine mesylate may be used concomitantly with Carbidopa-Levodopa, or with levodopa, in which case periodic dosage adjustment may be required in order to maintain optimum response.
Drug-Induced Extrapyramidal Disorders -
In treating extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), the recommended dosage is 1 to 4 mg once or twice a day orally, or parenterally. Dosage must be individualized according to the need of the patient. Some patients require more than recommended; others do not need as much.
In acute dystonic reactions, 1 to 2 mL of the injection usually relieves the condition quickly. After that, the tablets, 1 to 2 mg twice a day, usually prevents recurrence.
When extrapyramidal disorders develop soon after initiation of treatment with neuroleptic drugs (e.g., phenothiazines), they are likely to be transient. One to 2 mg of benztropine mesylate tablets two or three times a day usually provides relief within one or two days. After one or two weeks, the drug should be withdrawn to determine the continued need for it. If such disorders recur, benztropine mesylate can be reinstituted.
Certain drug-induced extrapyramidal disorders that develop slowly may not respond to benztropine mesylate.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 OR LEADING PHARMA, AT 1-844-740-7500.
Close BENZTROPINE MESYLATE Tablet [REMEDYREPACK INC.]ETODOLAC Tablet, Film Coated, Extended Release [Bryant Ranch Prepack]
A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy.
In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are:
gastrointestinal experiences including:
other events including:
* Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials.
Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include
Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis
Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic)
Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis
Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia
Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients
Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia
Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash
Special senses - blurred vision, photophobia, transient visual disturbances
Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency
Other NSAID Adverse Reactions, Which Occur Rarely Are
Body as a whole - anaphylactic reactions, appetite changes, death
Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction
Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis
Hemic and lymphatic system - aplastic anemia, lymphadenopathy
Metabolic and nutritional - change in weight
Nervous system - coma, convulsions, hallucinations, meningitis
Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis
Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis
Special senses - conjunctivitis, deafness, hearing impairment, taste perversion
Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities
CELECOXIB Capsule [Cambridge Therapeutics Technologies, LLC]
The following adverse reactions are discussed in greater detail in other sections of the labeling:
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Of the celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.
Pre-marketing Controlled Arthritis Trials
Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.
In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.
The following adverse reactions occurred in 0.1 to 1.9% of patients treated with celecoxib (100 to 200 mg twice daily or 200 mg once daily):
Gastrointestinal: Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting
Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction
General: Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain
Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo
Hearing and vestibular: Deafness, tinnitus
Heart rate and rhythm: Palpitation, tachycardia
Liver and biliary: Hepatic enzyme increased (including SGOT increased, SGPT increased)
Metabolic and nutritional: BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased
Musculoskeletal: Arthralgia, arthrosis, myalgia, synovitis, tendinitis
Platelets (bleeding or clotting): Ecchymosis, epistaxis, thrombocythemia,
Psychiatric: Anorexia, anxiety, appetite increased, depression, nervousness, somnolence
Hemic: Anemia
Respiratory: Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnea, laryngitis, pneumonia
Skin and appendages: Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria
Application site disorders: Cellulitis, dermatitis contact
Urinary: Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus
The following serious adverse events (causality not evaluated) occurred in <0.1% of patients:
Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis
Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus
General: Sepsis, sudden death
Liver and biliary: Cholelithiasis
Hemic and lymphatic: Thrombocytopenia
Nervous: Ataxia, suicide [see Drug Interactions (7.1)]
Renal: Acute renal failure
The Celecoxib Long-Term Arthritis Safety Study [see Special Studies (14.6)]
Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without aspirin use [see Clinical Pharmacology (12.2)].
Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively).
Juvenile Rheumatoid Arthritis Study
In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups.
In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged.
Other Pre-Approval Studies
Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies.
Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.
The APC and PreSAP Trials
Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [see Special Studies Adenomatous Polyp Prevention Studies (14.6)].
Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows:
The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:
Nervous system disorders: Cerebral infarction
Eye disorders: Vitreous floaters, conjunctival hemorrhage
Ear and labyrinth: Labyrinthitis
Cardiac disorders: Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy
Vascular disorders: Deep vein thrombosis
Reproductive system and breast disorders: Ovarian cyst
Investigations: Blood potassium increased, blood sodium increased, blood testosterone decreased
Injury, poisoning and procedural complications: Epicondylitis, tendon rupture
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