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

(Posted: 2/20/2002)

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[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/jul01.htm#actos ]

Pharmacodynamics and Clinical Effects moved to PRECAUTIONS, under a new section heading Weight Gain. The information was assembled in tabular form and included medians, 25% and 75% percentiles.

[See PRECAUTIONS below]

In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction.

Cardiac section deleted and the following new Cardiovascular section included:

In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported.

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CAFCIT (caffeine citrate) Injection & Oral Solution

[January 18, 2002: O.P.R. Development, L.P. c/o Roxane Laboratories]

Special Populations: Studies examining the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted. CAFCIT (caffeine citrate) should be administered with caution in preterm neonates with impaired renal or hepatic function.

CAFCITshould be administered with caution in infants with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of CAFCIT should be adjusted to avoid toxicity in this population. (See CLINICAL PHARMACOLOGY, Elimination, Special Populations).

Following overdosage, serum caffeine levels have ranged from approximately 24 mg/L (a post-marketing spontaneous case report in which an infant exhibited irritability, poor feeding and insomnia) to 350 mg/L. Serious toxicity has been associated with serum levels greater than 50 mg/L (see PRECAUTIONS-Laboratory tests and DOSAGE ADMINISTRATION). Signs and symptoms reported in the literature after caffeine overdosage in preterm infants include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated blood urea nitrogen, and elevated total leukocyte concentration. Seizures have also been reported in cases of overdose. One case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurologic sequelae has been reported. Another case

of caffeine citrate overdose (from New Zealand; not CAFCIT) of an estimated 600 mg caffeine citrate (approximately 322 mg/kg) administered over 40 minutes was complicated by tachycardia, ST depression, respiratory distress, heart failure, gastric distention, acidosis, and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site. No deaths associated with caffeine overdose have been reported in preterm infants.

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Added to the post-marketing experience section:

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Carcinogenesis, Mutagenesis, and Impairment of Fertility: Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. Claforan was not mutagenic in the mouse micronucleus test or in the Ame's test. Claforan did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m² ) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m²).

Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in pregnant mice given Claforan intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m²) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m²). No evidence of embryotoxicity or teratogenicity was seen in these studies.

ADVERSE REACTIONS Added: a list of cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).

[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/aug01.htm#clozar ]

Dear Healthcare Professional Letter (Feb 2002): http://www.fda.gov/medwatch/SAFETY/2002/Clozaril_deardoc.pdf

Revised Package Insert (Feb 2002):
http://www.fda.gov/medwatch/SAFETY/2002/Clozaril_PI.pdf

The previously existing BOXED WARNING has been relocated to the beginning of the package insert and revised to advise health care providers of the association of myocarditis with clozapine therapy. A subsection has been added to the WARNINGS section entitled "Myocarditis" to provide data and clozapine treatment guidelines related to this issue.

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[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#crixiv ]

Clinical Trials in Adults

First paragraph changed from:

To the following:

ADVERSE REACTIONS:

Urogenital System - pyelonephritis with or without bacteremia was added.

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Excretion: Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant.

Daypro is contraindicated in patients with known hypersensitivity to oxaprozin. Daypro should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

ACE-inhibitors: Reports suggest that NSAMs may diminish the antihypertensive effect of ACE-inhibitors. Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC _0-24 and C_max and its active metabolite enalaprilat (significant increase in dose-adjusted AUC _0-24 . This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Second paragraph -

The pharmacokinetic profile and tolerability of oxaprozin were assessed in IRA patients 6-16 years of age relative to adult rheumatoid arthritis patients in a 1.4 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in IRA

patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight (see Pharmacokinetics: Pediatric patients). No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of IRA patients and were somewhat more frequent when compared to the versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most 4f the adverse events were related to the gastrointestinal tract and were mild to moderate.

Third paragraph, first sentence -

In a 3 month open label study, 10 - 20 mg/kg/day of oxaprozin were administered to 59 IRA patients aged 3-16 years.

Second paragraph, first sentence -

Of the total number of subjects evaluated in four placebo controlled and active clinical studies of oxaprozin, 34 39% were 65 and over, and 11% were 75 and over.

New fourth paragraph -

The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs (double asterisks**).

Cardiovascular system: edema, blood pressure changes, congestive heart failure**, hypertension**, palpitations, tachycardia**, syncope**.

Hematologic system: agranulocytosis, anemia, ecchymosis, eosinophilia **, melena**, pancyropenia, purpura**, thrombocytopenia, leukopenia.

Metabolic system: weight changes.

Nervous system: anxiety**, asthenia**, confusion**, depression**, dream abnormalities**, drowsiness**, insomnia**, malaise, nervousness**, paresthesia**, somnolence**, tremors**, vertigo**, weakness.

Respiratory system: asthma**, dyspnea**, pulmonary infections, pneumonia**, sinusitis, symptoms of upper respiratory tract infection, respiratory depression**.

Skin: alopecia, angioedema**, pruritus, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat"**, toxic epidermal necrolysis (Lyell's syndrome).

Urogenital: acute interstitial nephritis, cystitis**, dysuria**, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria**, proteinuria**, renal insufficiency, acute renal failure, decreased menstrual flow.

First paragraph, last sentence added -

First paragraph, third sentence revised and fourth sentence added:

In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage

should be individualized to the lowest effective dose of Daypro to minimize adverse effects. The maximum recommended total daily dose of Daypro in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied.

Third paragraph, first sentence revised:

In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allow therapy to be started with a one-time loading dose of 1200 to 1800 mg (not to exceed 26 mg/kg).

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Geriatric Use:

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Geriatric Use: Clinical studies of DIPENTUM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patents.

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Boxed WARNING

End of the fourth paragraph, the following has been added:

Second sentence of the first paragraph revised:

From: Anemia was the most common hematologic adverse event (52.6%), followed by neutropenia (51.7%), leukopenia (WBC < 4000 mm3; 42.2%), and thrombocytopenia (24.2%).

To: Anemia was the most common hematologic adverse event (52.6%), followed by leukopenia (WBC < 4000 mm³; 42.2%), thrombocytopenia (24.2%), and neutropenia [ANC < 1000] (19.0%) (See Hemotology Data table in ADVERSE REACTIONS, Ovarian Cancer Patients.)

Reactions were added to the first sentence of the first paragraph:

Acute infusion-related reactions, characterized by flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritis, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and/or hypotension have occurred in 5% to 10% of patients treated with Doxil.

Second paragraph was added as follows:

Hematology Data Reported in Ovarian Cancer Patients table, the Leukopenia category was deleted and the Neutropenia category of < 2000 mm3 was replaced with a category of < 1000 mm³.

Hematology Data Reported in AIDS-KS Patients table, the Leukopenia category was deleted and the Neutropenia category of < 2000 mm³ was replaced with a category of <1000 mm³.

[Other labeling changes not appearing in 2001 PDR:
http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#glucop, http://www.fda.gov/medwatch/safety/2000/dec00.htm#glucop]

Patients should be informed that Glucophage XR must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

DOSAGE AND ADMINISTRATION:

GLUCOPHAGE XR tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR will be eliminated in the feces as a soft, hydrated mass. (See Patient Information Printed Below).

GLUCOPHAGE XR must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way GLUCOPAHGE XR works to control your diabetes.

Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. There have been reports of priapism and thrombocytopenia during post-marketing surveillance. Atrial fibrillation has been reported.

Labeling contains 48-week safety and efficacy data (updated from 24-week data) from three studies included in the original NDA. These supplements provide for the use of KALETRA Capsules and KALETRA Oral Solution in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in a controlled study of KALETRA of 48 weeks duration and in smaller uncontrolled dose-ranging studies of KALETRA of 72 weeks duration. At present, there are no results from controlled trials evaluating the effect of KALETRA on clinical progression of HIV.

KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in a controlled study of KALETRA of 242424 48 weeks duration and in smaller uncontrolled dose-ranging studies of KALETRA of 72 weeks duration. At present, there are no results from controlled trials evaluating the effect of KALETRA on clinical progression of HIV.

Figure 2: Virologic Response Through 24 WEEKS (Study 863) 24 Weeks (Study 863)Week 48, Study 863*^†

 

Table 3: 3:4: Outcomes of Randomized Treatment Through Week 24 - 24 -48 (Study 863)

Through 24Through 24 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 154 154207 cells/mm³ for the KALETRA arm and 150 150195 cells/mm³ for the nelfinavir arm.

KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Through 24 2448 weeks of therapy, the proportion of patients withwho achieved and sustained an HIV RNA < 400 copies/mL was 82 82%80% for antiretroviral naive patients and 66 66%71% for antiretroviral experienced patients. The mean increase from baseline in CD4 cell count was 328 328404 cells/mm³ for antiretroviral naive and 335335 284cells/mm³ for antiretroviral experienced patients treated through 24 24 weeks. At 24 weeks, one patient (1%)48 weeks. At 24 weeks, one patient (1%)At 48 weeks, two patients (2%) had prematurely discontinued the study. This discontinuation wasOne antiretroviral naive patient prematurely discontinued secondary to an adverse event attributed to KALETRA, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-relatedevent in an antiretroviral experienced patient that was not attributed to a KALETRA adverse event.

Treatment-Emergent Adverse Events: KALETRA has been studied in 612 patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with KALETRA therapy was diarrhea, which was generally of mild to moderate severity. Rates of discontinuation of randomized therapy due to adverse events were 2.8% in KALETRA and 3.1% in nelfinavir treated 2.8% in KALETRA and 3.1% in nelfinavir treated5.8% in KALETRA-treated and 4.9% in nelfinavir-treated patients in Study 863.

Drug related clinical adverse events of moderate or severe intensity in > 2% of patients treated with combination therapy including KALETRA for up to 24 2448 weeks (Phase III) and for up to 72 weeks (Phase I/II) are presented in Table 7.9. For other information regarding observed or potentially serious adverse events, please see WARNINGS and PRECAUTIONS.

Treatment-emergent adverse events occurring in less than 2% of adult patients receiving KALETRA in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with KALETRA and of at least moderate intensity are listed below by body system.

Body as a Whole: Back BackAbdomen enlarged, back pain, chest pain, chest pain substernal, chills, cyst, drug interaction, drug level increased, face edema, fever, flu syndrome, hypertrophy, infection bacterial, malaise, and viral infection.

Cardiovascular System: Deep vein thrombosis, hypertension, migraine, palpitation, thrombophlebitis, varicose vein, and vasculitis.

Digestive System: Anorexia, cholecystitis, constipation, dry mouth,dyspepsia, dyspepsia, dysphagia, enterocolitis, eructation, esophagitis, fecal incontinence, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, hemorrhagic colitis, increased appetite, mouth ulceration, pancreatitis, sialadenitis, stomatitis, and ulcerative stomatitis.

Endocrine System: Cushing’s syndrome, diabetes mellitus, and hypothyroidism.

Hemic and Lymphatic System: Anemia, leukopenia, and lymphadenopathy.

Metabolic and Nutritional Disorders: Avitaminosis, dehydration, edema, glucose tolerance decreased, lactic acidosis, obesity, peripheral edema, weight gain, and weight loss.

Musculoskeletal System: Arthralgia, arthrosis and myalgia.

Nervous System: Abnormal dreams, agitation, amnesia, anxiety, ataxia, confusion, depression, dizziness, dyskinesia, emotional lability, encephalopathy, facial paralysis, hypertonia, libido decreased, nervousness, neuropathy, paresthesia, peripheral neuritis, somnolence, thinking abnormal, and tremor.

Respiratory System: Bronchitis, dyspnea, lung edema, rhinitis, and sinusitis.

Skin and Appendages: Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhea, skin benign neoplasm, skin discoloration, skin ulcer, and sweating.

Special Senses: Abnormal vision, eye disorder, otitis media, taste perversion, and tinnitus.

Urogenital System: Abnormal ejaculation, gynecomastia, hypogonadism male, kidney calculus, and urine abnormality.

Post-Marketing Experience: Redistribution/accumulation of body fat has been reported (see PRECAUTIONS, Fat Redistribution).

Treatment-Emergent Adverse Events: KALETRA has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse event profile seen during a clinical trial was similar to that for adult patients.

Taste aversion, vomiting, and diarrhea were the most commonly reported drug related adverse events of any severity in pediatric patients treated with combination therapy including KALETRA for up to 48 weeks in Study 940. A total of 8 children experienced moderate or severe adverse events at least possibly related to Rash (2%)KALETRA. Rash (reported in 3%) was the only drug-related clinical adverse events of moderate orto severe intensity in > 2% of pediatric patients treated with combination therapy including KALETRA (300/75 mg/m²) for up to 24 weeks (Study 940). This includes adverse events of at least possible, probable or unknown relationship to study drug.observed in ³ 2% of children enrolled.

² Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.

Drug Interactions - "amiodarone" has been added to the first sentence of the third paragraph.

LOVENOX (enoxaparin sodium) Injection

[January 9, 2002: Aventis]

Prosthetic Heart Valves: The use of Lovenox Injection is not recommended for thromboprophylaxis in patients with prosthetic heart valves. Cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic valves who have received enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal deaths and fetal deaths. Pregnant women with prosthetic heart valves may be at higher risk for thromboembolism (see PRECAUTIONS: Pregnancy).

Second paragraph added:

First paragraph revised:

Non-teratogenic Effects: There have been a few spontaneous post-marketing reports of fetal death when pregnant women received enoxaparin. Causality of the cases has not been determined. In one case, placental hemorrhage and detachment were found in association with the fetal death. If enoxaparin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Second paragraph added:

Addition of "Nongonococcal urethritis, endocervical, or rectal infections in adults caused by Ureaplasma urealyticum or Chlamydia trachomatis."

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3.Carcinoma

Previous subsection replaced with the following:

Risks of Using the Norplant System section - Contact the company for a copy of the labeling/package insert.

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[Other safety related information regarding Oxycontin: http://www.fda.gov/medwatch/safety/2001/safety01.htm#oxycon]

Patient Information sheet added:

PATIENT INFORMATION

OXYCONTIN Schedule II

Read this information carefully before you take OxyContin (ox-e-CON-tin) tablets. Also read the information you get with your refills. There may be something new. This information does not take the place of talking with your doctor about your medical condition or your treatment. Only you and your doctor can decide if OxyContin is right for you. Share the important information in this leaflet with members of your household.

• Swallow the tablets whole. Do not break, crush, dissolve, or chew them before swallowing.

OxyContin works properly over 12 hours only when swallowed whole. If a tablet is broken, crushed, dissolved, or chewed, the entire 12 hour dose will be absorbed into your body all at once. This can be dangerous, causing an overdose, and possibly death.

• Keep OxyContin out of the reach of children. Accidental overdose by a child is dangerous and may result in death.

• Prevent theft and misuse. OxyContin contains a narcotic painkiller that can be a target for people who abuse prescription medicines. Therefore, keep your tablets in a secure place, to protect them from theft. Never give them to anyone else . Selling or giving away this medicine is dangerous and against the law.

OxyContin is a tablet that comes in several strengths and contains the medicine oxycodone (ox-e-KOE- done). This medicine is a painkiller like morphine. OxyContin treats moderate to severe pain that is expected to last for an extended period of time. Use OxyContin regularly during treatment. It contains enough medicine to last for up to twelve hours.

Do not take OxyContin if

· your doctor did not prescribe OxyContin for you.

· your pain is mild or will go away in a few days.

· your pain can be controlled by occasional use of other painkillers.

· you have severe asthma or severe lung problems.

· you have had a severe allergic reaction to codeine, hydrocodone, dihydrocodeine, or oxycodone (such as Tylox, Tylenol with Codeine, or Vicodin. A severe allergic reaction includes a severe rash, hives, breathing problems, or dizziness.

· you had surgery less than 12 - 24 hours ago and you were not taking OxyContin just before surgery.

Your doctor should know about all your medical conditions before deciding if OxyContin is right for you and what dose is best. Tell your doctor about all of your medical problems, especially the ones listed below:

· trouble breathing or lung problems

· head injury

· liver or kidney problems

· adrenal gland problems, such as Addison’s disease

· convulsions or seizures

· alcoholism

· hallucinations or other severe mental problems

· past or present substance abuse or drug addiction

If any of these conditions apply to you, and you haven’t told your doctor, then you should tell your doctor before taking OxyContin.

If you are pregnant or plan to become pregnant, talk with your doctor. OxyContin may not be right for you. Tell your doctor if you are breast feeding. OxyContin will pass through the milk and may harm the baby.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. They may cause serious medical problems when taken with OxyContin, especially if they cause drowsiness.

· Follow your doctor’s directions exactly. Your doctor may change your dose based on your reactions to the medicine. Do not change your dose unless your doctor tells you to change it. Do not take OxyContin more often than prescribed.

· Swallow the tablets whole. Do not break, crush, dissolve, or chew before swallowing. If the tablets are not whole, your body will absorb too much medicine at one time. This can lead to serious problems, including overdose and death.

· If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once unless your doctor tells you to.

· In case of overdose, call your local emergency number or poison control center right away.

· Review your pain regularly with your doctor to determine if you still need OxyContin.

· You may see tablets in your stools (bowel movements). Do not be concerned. Your body has already absorbed the medicine.

Stopping OxyContin. Consult your doctor for instructions on how to stop this medicine slowly to avoid uncomfortable symptoms. You should not stop taking OxyContin all at once if you have been taking it for more than a few days.

After you stop taking OxyContin, flush the unused tablets down the toilet.

· Do not drive, operate heavy machinery, or participate in any other possibly dangerous activities until you know how you react to this medicine. OxyContin can make you sleepy.

· Do not drink alcohol while using OxyContin. It may increase the chance of getting dangerous side effects.

· Do not take other medicines without your doctor’s approval. Other medicines include prescription and non-prescription medicines, vitamins, and supplements. Be especially careful about products that make you sleepy.

What are the Possible Side Effects of OxyContin?

• your breathing slows down

• you feel faint, dizzy, confused, or have any other unusual symptoms

Some of the common side effects of OxyContin are nausea, vomiting, dizziness, drowsiness, constipation, itching, dry mouth, sweating, weakness, and headache. Some of these side effects may decrease with continued use.

There is a risk of abuse or addiction with narcotic painkillers. If you have abused drugs in the past, you may have a higher chance of developing abuse or addiction again while using OxyContin. We do not know how often patients with continuing (chronic) pain become addicted to narcotics, but the risk has been reported to be small.

These are not all the possible side effects of OxyContin. For a complete list, ask your doctor or pharmacist.

• Do not use OxyContin for conditions for which it was not prescribed.

• Do not give OxyContin to other people, even if they have the same symptoms you have. Sharing is illegal and may cause severe medical problems, including death.

This leaflet summarizes the most important information about OxyContin. If you would like more information, talk with your doctor. Also, you can ask your pharmacist or doctor for information about OxyContin that is written for health professionals.

Added: fever

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Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg PRANDIN (after 4 days of once daily simvastatin 20 mg and three times daily Prandin 2 mg) resulted in a 26% increase in repaglinide Cmax from 23.6 ng/ml to 29.7 ng/ml. AUC was unchanged.

Measures of AUC and Cmax after multiple dosing of 2 mg repaglinide were found to be higher in three groups of patients with reduced renal function: (AUCrmild/moderate impairment: 90.8 ng/mL*hr to AUCsevere impairment: 137.7 ng/mL*hr versus AUChealthy:29.1 ng/mL*hr; Cmax, mild/moderate impairment: 46.7 ng/mL to Cmax, severe impairment: 44.0 ng/mL versus Cmax, healthy :20.6 ng/mL). Repaglinide AUC is only weakly correlated to creatinine clearance. Initial dosage adjustment does not appear to be necessary, but Subsequent increases in PRANDIN should be made carefully in patients with type 2 diabetes who have renal function impairment or renal failure requiring hemodialysis.

Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mg/dL), mild to moderate renal function impairment (CrCl = 40 – 80 mg/dL), and severe renal function impairment (CrCl = 20 – 40 mg/dL). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL *hr vs 57.2 ng/mL *hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mL *hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction.

However, patients with type 2 diabetes who have severe renal function impairment should initiate PRANDIN therapy with the 0.5 mg dose – subsequently, patients should be carefully titrated. Studies were not conducted in patients with creatinine clearances below 20 mg/mL or patients with renal failure requiring hemodialysis.

Hepatic insufficiency. A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance.

Last paragraph revised:

4. Revisions to the PRECAUTIONS section, Drug-Drug Interactions subsection.

5. Revision to the ADVERSE REACTIONS section, Infrequent Adverse Events subsection, to include several rare, spontaneously reported post-marketing adverse events.

In vitro data indicate that repaglinide metabolism may be inhibited by antifungal agents like ketoconazole and miconazole, and antibacterial agents like erythromycin (cytochrome P450 3A4 inhibitors). Drugs that induce the cytochrome P450 enzyme system 3A4 may increase repaglinide metabolism; such drugs include troglitazone, rifampin, barbiturates, and carbamazepine. No systematically acquired data are available on increased or decreased plasma levels with 3A4 inhibitors or inducers See CLINICAL PHARMACOLOGY section, Drug-Drug Interactions.

5. Revision to the ADVERSE REACTIONS section, Infrequent Adverse Events subsection, to include several rare, spontaneously reported post-marketing adverse events.

Although no causal relationship has been established, postmarketing experience includes reports of the following rare adverse events: alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction.

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Labeling provides for revisions to the prescriber labeling regarding Serzone and hepatic failure to incorporate a patient package insert and a "Dear Healthcare Practitioner" letter. Use the links below to see complete revised prescribing information.

"Dear Healthcare Practitioner" letter: http://www.fda.gov/medwatch/SAFETY/2002/serzone_deardoc.PDF

Full Revised Serzone Label: http://www.fda.gov/medwatch/SAFETY/2002/serzone_label.pdf

Patient Package Insert: http://www.fda.gov/medwatch/SAFETY/2002/serzone_PPI.pdf

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[Other labeling changes not appearing in 2001 PDR:
http://www.fda.gov/medwatch/SAFETY/2001/jan01.htm#stadol]

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Labeling provides for a name change from Bio-Tropin to Tev-Tropin.

In Vivo Studies: (paragraph 4)

[Other labeling changes not appearing in 2001 PDR:

http://www.fda.gov/medwatch/SAFETY/2001/nov01.htm#videx]

Labeling provides for the inclusion of safety and efficacy data from the final results of study AI454-152 in the VIDEX EC (didanosine) Delayed Release Capsules package insert. Contact the company for a copy of the labeling/package insert.

Labeling provides for the use of Xopenex (levalbuterol inhalation solution) for the treatment or prevention of bronchospasm in children 6 years of age and older with reversible obstructive airway disease. Contact the company for a copy of the labeling/package insert.

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[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/may01.htm#zantac]

Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and vasculitis.

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[Other labeling changes not appearing in 2001 PDR:

CLINICAL PHARMACOLOGY

Special Populations

Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).

PRECAUTIONS

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Acyclovir was tested in 16 in vitro and in vivo  genetic toxicity assays. Acyclovir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per day, PO) or in rats (25 mg/kg per day, SC). In the mouse study, plasma levels were the same as human levels, while in the rat study, they were 1 to 2 times human levels. At higher doses (50 mg/kg per day, SC) in rats and rabbits (1 to 2 and 1 to 3 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.

First paragraph:

Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC).

There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy has collected data since June 1984. As of December 1997, outcomes of live births have been documented in 552 women has collected data since June 1984. As of December 1997, outcomes of live births have been documented in 552 women was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in pregnancy.756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for specific specific less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.  Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Geriatric Use: Clinical studies of ZOVIRAX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than 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 renal function, and of concomitant disease or other drug therapy.

Geriatric Use: Clinical studies of ZOVIRAX for Injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has identified differences in the severity of CNS adverse events between elderly and younger patients (see ADVERSE REACTIONS: Observed During Clinical Practice). In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

General: angioedema

Digestive: Diarrhea, elevated liver function tests, elevated liver function tests, gastrointestinal distress, nausea

Hematologic and Lymphatic: Disseminated intravascular coagulation, hemolysis, leukocytoclastic vasculitis, leukopenia, lymphadenopathy.

Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.

Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, encephalopathy, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence, tremor. These symptoms may be marked, particularly in older adults (see PRECAUTIONS).

Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of ZOVIRAX into extravascular tissues.

 

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