Summary Of Safety-Related Drug Labeling
Changes Approved By FDA Center for Drug
Evaluation and Research (CDER)
May 2002

(Posted: 07/03/2002)

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[Other labeling changes not found 2002 PDR:

http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#accuta,

http://www.fda.gov/medwatch/SAFETY/2002/apr02.htm#accuta]

SKIN/APPENDAGES: rash (Maculopapular, purpuric, pustular) added

Additional clinically relevant rare events, judged by investigators to be at least possibly drug-related, that occurred in less than 0.1% of moxifloxacin treated patients were: pelvic pain, face edema, vasodilation, hypotension, hallucinations, depersonalization, hypertonia, incoordination, agitation, amnesia, ventricular tachycardia, atrial fibrillation, supraventricular tachycardia abnormal dreams, abnormal vision, agitation, amblyopia, amnesia, anemia, aphasia, arthritis, asthma, atrial fibrillation, convulsions, depersonalization, depression, diarrhea (Clostridium difficile), dysphagia, ECG abnormal, emotional lability, aphasia, thinking abnormal, abnormal dreams, abnormal vision, convulsions, hypesthesia, depression, gastrtisi, tongue discoloration, dysphagia, jaundice, diarrhea(Clostridium difficile), prothrombin increase, anemia, face edema, gastritis, hallucinations, hyperglycemia, hyperlipidemia, hypertonia, hyperuricemia, arthritis, tendon disorder, asthma, tinnitus, parosmia, taste loss, amblyopia, hypesthesia, hypotension, incoordination, jaundice, kidney function abnormal urticaria, parosmia, pelvic pain, prothrombin increase, sleep disorders, speech disorders, supraventricular tachycardia, taste loss, tendon disorder, thinking abnormal, thromboplastin decrease, tinnitus, tongue discoloration, urticaria, vasodilatation, ventricular tachycardia.

[May 16, 2002: Pharmacia & Upjohn]

[see safety related and labeling information at http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#campto]

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Added "atorvastatin†" and "pravastatin†"

Added "miconazole (intravaginal, systemic) "

Added "Fungal Medications, Intravaginal, Systemic†"

Bromelains, danshen, dong quai (Angelica sinensis), garlic, and Ginkgo biloba, and ginseng are associated most often with an INCREASE in the effects of COUMADIN.

Pharmacokinetics:

Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation and glucuronidation. The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquin which is mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism–ie, 7-10% of Caucasians and a low percentage of Asians have little or no activity and are called "poor metabolizers". Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or "extensive" metabolizers.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with (antipsychotic) drugs. Older patients are at increased risk for development of tardive dyskinesia.

Given these considerations, especially in the elderly, antipsychotics neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Geriatric Use: Clinical studies of ETRAFON products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects 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 and renal function, concomitant disease or other drug therapy.

Elderly patients: With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Dosing of perphenazine may occur before bedtime if required.

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In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. In another drug interaction study, coadministration of orally inhaled fluticasone propionate (1000 mcg, 5 times the maximum daily intranasal dose) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. and reduced plasma cortisol area under the plasma concentration versus time curve (AUC), but had no effect on urinary excretion of cortisol. Due to very low plasma concentrations achieved after intranasal dosing, clinically significant drug interactions are unlikely; however, S since fluticasone propionate is a substrate of cytochrome P450 3A4, caution should be exercised when known strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole) are coadministered with fluticasone propionate as this could result in increased plasma concentrations of fluticasone propionate.

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Addition of the terms "aggression, anger, and irritability".

[Other labeling changes not found in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#minoci,

http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#minoci]

Geriatric use: Clinical studies of minocycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 (see WARNINGS, DOSAGE AND ADMINISTRATION).

Pediatric Use: [NASALIDE/NASAREL] is not recommended for use in pediatric patients less than 6 years of age as safety and efficacy have not been assessed in this age group. [NASAREL] For pediatric patients 6 years of age and over, recommended maximum daily doses should not be exceeded in order to minimize the risk of systemic corticoid effect, including potential growth retardation. (See INDIVIDUALIZATION OF DOSAGE and DOSAGE AND ADMINISTARATION.) [NASALIDE/NASAREL] Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including [NASALIDE/NASAREL], should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including NASALIDE/NASAREL], each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

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Absorption and Distribution: Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average

Metabolism: Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion: Studies in women receiving 20 mg of ¹⁴ C tamoxifen have shown that

Special Populations: The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Drug-drug Interactions: In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K₁ of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.

(see BOXED WARNING at the beginning of the label)

Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma:

An increased incidence of uterine malignancies has been reported in association with NOLVADEX treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of NOLVADEX. Most uterine malignancies seen in association with NOLVADEX are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (³ 2 years) of NOLVADEX than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal.

In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27- 4.92). The 33 cases in participants receiving NOLVADEX were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on Nolvadex and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78 - 13.16). Among women £ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28 - 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants £ 49 randomized to NOLVADEX compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women ³ 50 at the time of diagnosis, there were 29 cases among participants randomized to NOLVADEX compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the NOLVADEX group occurred in asymptomatic women. Among women receiving NOLVADEX the events appeared between 1 and 61 months (average=32 months) from the start of treatment.

Any patient receiving or who has previously received NOLVADEX who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received NOLVADEX should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, eg, menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure.

In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking NOLVADEX to reduce the incidence of breast cancer would be beneficial.

As with other additive hormonal therapy (estrogen), t There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during NOLVADEX therapy.

NOLVADEX may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking NOLVADEX or within 2 months of discontinuing NOLVADEX and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m ² basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations.

In rodent models of fetal reproductive tract development, tamoxifen (at dose 0.3 0.002 to 2.4 -fold the daily maximum recommended human dose on a mg/m ² basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol.

Women who are pregnant or who plan to become pregnant should not take NOLVADEX to reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking NOLVADEX and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, NOLVADEX therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (See WARNINGS-Pregnancy Category D).

Tamoxifen, N-desmethyl tamoxifen and 4-Hydroxytamoxifen have been found to be potent inhibitors of hepatic cytochrome p-450 mixed function oxidases. Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with

One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

Endocrine changes in immature and mature mice were investigated in a 13-month study. Granulosa cell ovarian tumors and interstitial cell testicular tumors were found in mice receiving NOLVADEX, but not in the controls. observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m ² basis).

Although n No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems present However, increased levels of DNA adducts were observed by ³²P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.

Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with NOLVADEX therapy. In some of these cases, the time to onset was more than one year.

Like all medicines, NOLVADEX has some side effects. Most are mild and relate to its hormonal mode of action. For all women NOLVADEX can, however, also increase the risk of some serious and potentially life-threatening conditions events, including uterine cancer, blood clots, and stroke. Some of these events have caused death. It NOLVADEX can also increase the risk of getting cataracts or of needing cataract surgery. If you experience symptoms of any of these, tell your doctor immediately (see "What should I avoid or do while taking NOLVADEX?").

You should not take NOLVADEX to reduce the risk of getting breast cancer if you are taking medicines to thin your blood (anticoagulants) like warfarin (Coumadin*).

You should not become pregnant when taking Nolvadex or during the two months after you stop taking it as Nolvadex may harm your unborn child. Please contact your doctor for birth control recommendations. Tamoxifen does not prevent pregnancy, even in the presence of menstrual irregularity.

If you see a health care professional who is new to you (an emergency room doctor, another doctor in the practice), tell him or her that you take NOLVADEX or have previously taken NOLVADEX.

While you are taking NOLVADEX and after you stop taking NOLVADEX and in keeping with your doctor’s recommendation, you should have annual gynecological check-ups which should include breast exams and mammograms.

Women may experience hair loss, skin rashes (itching or peeling skin) or headaches; or inflammation of the lungs, which may have the same symptoms as pneumonia, such as breathlessness and cough; however, hair loss is uncommon and is usually mild.

NOLVADEX increases the chance of changes occurring in the lining (endometrium) or body of your uterus which can be serious and could include cancer of the uterus. If you have not had a hysterectomy (removal of the uterus), it is important for you to contact your doctor immediately if you experience any unusual vaginal discharge, vaginal bleeding, or menstrual irregularities; or pain or pressure in the pelvis (lower stomach). These may be caused by changes to the lining (endometrium) or body of your uterus. It is important to bring them to your doctor’s attention without delay as they can occasionally indicate the start of something more serious and even life-threatening and could include cancer of the uterus or other changes to the uterus.

General: allergic reaction, asthenia, **back pain, hot flushes, malaise, pain rigors, weight gain, weight decrease.

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"Over 800 4000 women were treated with lansoprazole. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse events were also similar to those seen in males."

Worldwide, over 6100 10,000 patients have been treated with lansoprazole in Phase 2-3 clinical trials involving various dosages and durations of treatment. The adverse reaction profiles for PREVACID Delayed-Release Capsules and PREVACID for Delayed-Release Oral Suspension are similar. In general, lansoprazole treatment has been tolerated in both short-term and long-term trials.

"Body as a Whole" – abdomen enlarged, allergic reaction, asthenia, candidiasis, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain; Cardiovascular System - angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/ hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, vasodilation; Digestive System – abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, constipation, dry mouth/thirst, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis; Endocrine System - diabetes mellitus, goiter, hyperglycemia/hypoglycemia, hypothyroidism; Hemic and Lymphatic System - anemia, hemolysis, lymphadenopathy; Metabolic and Nutritional Disorders - gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss; Musculoskeletal System - arthritis/arthralgia, arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia myasthenia, synovitis; Nervous System -– abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, depersonalization, depression, diplopia, dizziness/syncope, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality tremor, vertigo; Respiratory System - asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, pharyngitis, pleural disorder; pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor; Skin and Appendages - acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria; Special Senses - abnormal vision, blurred vision, conjunctivitis, deafness, dry eyes, ear disorder, eye pain, otitis media, parosmia, photophobia, retinal degeneration, taste loss, taste perversion, tinnitus, visual field defect; Urogenital System - abnormal menses, albuminuria, breast enlargement/gynecomastia, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, glycosuria, hematuria, impotence, kidney calculus kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency urinary tract infection, urinary urgency, urination impaired, vaginitis.

"The following changes in laboratory parameters for lansoprazole were reported as adverse events: Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, and increased gastrin levels. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (1/250) (4/978) placebo patients and 0.3% (2/795) 0.4% (11/2677) lansoprazole patients had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these lansoprazole patients reported jaundice at any time during the study."

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In a single center, randomized, two-period crossover study with 42 healthy volunteers (31 males, 11 females), a single 400mg Skelaxin (metaxalone) tablet was administered under both fasted and fed conditions. Under fasted conditions, mean ± S.D. peak plasma metaxalone concentrations (C_max) of 983.4 ± 516.9 ng/mL were achieved within 3.3 ± 1.2 hours after dosing (T_max). Metaxalone concentrations declined with mean terminal half-life (T_1/2) of 9.0 ± 4.8 hours. The mean apparent oral clearance (CL/F) of metaxalone was 53.5 ± 27.1 L/hr. In the same study, the administration of a 400 mg Skelaxin tablet following a standardized high fat meal showed an increase in the mean Cmax and the area under the curve (AUC0-t) of metaxalone to 177.5% and 123.5%, respectively. The mean T_max was also increased to 4.3 ± 2.3 hr, whereas the mean T_1/2 was decreased to 2.4 ± 1.2 hr. Given the magnitude of plasma level changes following a high fat meal, Skelaxin tablets should be administered on an empty stomach.

The absolute bioavailability of Skelaxin tablets is not known. Metaxalone is metabolized by the liver and excreted in urine as unidentified metabolites. The impact of age, gender, hepatic and renal disease on the pharmacokinetics of Skelaxin tablets has not been determined at this time.

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Microbiology subsection revised, with some revisions extensive. Contact the company for a copy of the new labeling package insert.

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Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Older patients are at increased risk for development of tardive dyskinesia. 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.

Given these considerations, especially in the elderly, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Drug Interactions: Metabolism of a number of medications, including antipsychotics, antidepressants, b - blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called "poor" metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.

The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g.fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.

Elderly patients: With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration. Dosing of perphenazine may occur before bedtime, if required.

OVERDOSAGE In the event of overdosage, emergency treatment should be started immediately. Consultation with a poison center should be considered. All patients suspected of having taken an overdose should be hospitalized as soon as possible.

Manifestations The toxic effects of perphenazine are typically mild to moderate with death occurring in cases involving a large overdose. Overdosage of perphenazine primarily involves the extrapyramidal mechanism and produces the same side effects described under ADVERSE REACTIONS, but to a more marked degree. It is usually evidenced by stupor or coma; children may have convulsive seizures. Signs of arousal may not occur for 48 hours. The primary effects of medical concern are cardiac in origin including tachycardia, prolongation of the QRS or QTc intervals, atrioventricular block, torsade de pointes, ventricular dysrhythmia, hypotension or cardiac arrest, which indicate serious poisoning. Deaths by deliberate or accidental overdosage have occurred with this class of drugs.

Treatment Treatment is symptomatic and supportive. Induction of emesis is not recommended because of the possibility of a seizure, CNS depression, or dystonic reaction of the head or neck and subsequent aspiration. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. There is no specific antidote. The patient should be induced to vomit even if emesis has occurred spontaneously. Pharmacologic vomiting by the administration of ipecac syrup is a preferred method. It should be noted that ipecac has a central mode of action in addition to its local gastric irritant properties, and the central mode of action may be blocked by the antiemetic effect of TRILAFON products. Vomiting should not be induced in patients with impaired consciousness. The action of ipecac is facilitated by physical activity and by the administration of 8 to 12 fluid ounces of water. If emesis does not occur within 15 minutes, the dose of ipecac should be repeated. Precautions against aspiration must be taken, especially in infants and children. Following emesis, any drug remaining in the stomach may be adsorbed by activated charcoal administered as a slurry with water. If vomiting is unsuccessful or contraindicated, gastric lavage should be performed. Isotonic and one-half isotonic saline are the lavage solutions of choice. Saline cathartics, such as milk of magnesia, draw water into the bowel by osmosis and therefore, may be valuable for their action in rapid dilution of bowel content.

An electrocardiogram should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine, or propranolol. Digitalis should be considered for cardiac failure. Close monitoring of cardiac function is advisable for not less than five days. Vasopressors such as norepinephrine may be used to treat hypotension, but epinephrine should NOT be used.

Hemodialysis and peritoneal dialysis is of no value because of low plasma concentrations of the drug.

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental overdosage have occurred with this class of drugs.

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[Other labeling changes not found in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/mar02.htm#zocor]

Skeletal Muscle, subsection changed to Myopathy/Rhabdomyolysis.

· The risk of myopathy/rhabdomyolysis is dose related. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80 mg.

1. Use of simvastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

2. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses ( ³ 1 g/day) of niacin. The combined use of simvastatin with fibrates or niacin should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Addition of these drugs to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.

4. All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

5. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil (see WARNINGS, Myopathy/Rhabdomyolysis).

Concomitant Therapy changed to Concomitant Lipid-Lowering Therapy.

ZOCOR is effective alone or when used concomitantly with bile-acid sequestrants. If ZOCOR is used in combination with gemfibrozil, other fibrates or lipid-lowering doses³ 1 g/day) of niacin, the dose of ZOCOR should not exceed 10 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

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