---

BAYCOL (cerivastatin sodium)	FORTOVASE (saquinavir)	INVIRASE (saquinavir mesylate)	LACTATED RINGERS
LOVENOX (enoxaparin sodium)	METHOTREXATE	NAROPIN (ropivacaine HCl)	NAVELBINE (vinorelbine)
PREVACID (lansoprazole)	PRIMACOR (milrinone lactate)	PROZAC (fluoxetine HCl)	SARAFEM (fluoxatine HCl)
SUSTIVA (efavirenz)	TALACEN (pentazocine/ acetaminophen)	TAMIFLU (oseltamivir phosphate)	VIRAMUNE (nevirapine)
ZITHROMAX (azithromycin)	ZOCOR (simvastatin)	ZOLOFT (sertraline HCl)	ZYBAN (bupropion HCl)
ZYPREXA (olanzapine)

 

Baycol (cerivastatin sodium)

[November 6, 2000:Bayer Corporation]

[Other labeling changes not appearing in 2000 PDR: July 00 ]

Supplemental new drug application provides for the addition of a Patient Package Insert to the
labeling for this product. 

Read this information carefully before you start taking your medicine. Read the information you get with your medicine each time

you refill your prescription. There may be new information. This information does not take the place of talking with your doctor.

Baycol [BAY-call ]is a prescription medicine that reduces the total amount of cholesterol that your body makes. It also lowers

the level of your LDL (bad) cholesterol.Baycol is used by adults with high cholesterol, when diet and exercise have not low-

ered cholesterol enough. You should follow a diet low in fat and cholesterol and exercise regularly when taking Baycol.

Do not take Baycol if you

• Take Lopid ((gemfibrozil).

•Take certain other medicines. Tell your doctor about other medicines and supplements. You can get serious muscle prob-

lems that can lead to kidney failure if you take Baycol with some medicines. One of these medicines is Lopid (gemfibrozil).

• Are pregnant or breast feeding or if you may become pregnant. .Baycol may harm the baby.

• Have liver disease or possible liver problems..

Tell your doctor if you had liver problems in the past or if you drink a lot of alcohol (three (3)or more drinks per day).Your

doctor may want to start you on the lower doses of Baycol and check you more often.

Tell your doctor if you will have major surgery, have been badly injured, have epilepsy, problems with your hormones or seri-

ous kidney problems. You may need to stop taking Baycol for a while.

Children should not take Baycol.

Take Baycol once a day in the evening, at about the same time each day. Swallow it whole with liquid. You can take it with or

without food.

If you miss your daily dose, do not take two doses the next day. Rather, skip the dose and go back to your regular schedule on

the next day. Do not take 2 doses at one time.

Continue with your diet and exercise program while taking Baycol.

Your doctor may do blood tests to check for liver problems before you start taking Baycol, at 6 and 12 weeks after you start

taking it, and then every 6 months. Your blood should also be checked if your dose is increased.

Do not

• Take Lopid (gemfibrozil).

• Breast feed since Baycol can pass through the milk and may harm the baby.

•Take Baycol while you are pregnant. If you become pregnant while taking Baycol, stop taking it and tell your doctor right away.

• Take certain other medicines.. Ask your doctor what medicines you should not take.

The most common complaints from patients taking Baycol are headache, sore throat, runny nose, stuffy nose, joint and muscle

pain, diarrhea, and rash. If you develop these or other symptoms that you think may be caused by Baycol, contact your doctor.

Muscle and kidney problems. If you experience any unexplained muscle pain, tenderness, or weakness at any time during

treatment with Baycol, you should notify your doctor immediately. Rarely, there is a risk of muscle breakdown resulting in kid-

ney damage. The risk of this breakdown is greater in patients taking certain other drugs along with Baycol such as Lopid 

(gemfibrozil) as well as cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or lipid-lowering doses of niacin. If

you are uncertain whether you are taking one of these medications, speak with your doctor. Because of these risks, your doc-

tor should carefully monitor you for any muscle pain, tenderness or weakness, particularly during the initial months of treat-

ment, if the dose of Baycol is increased, or if you are a woman over 65 years of age.

Tell your doctor right away if you get unexpected muscle pain, tenderness or weakness, especially if you also have a fever or

feel sick. These may be sign of a serious side effect.

Liver problems Some patients taking Baycol have blood tests that show possible liver problems.Your doctor will check your

liver function with blood tests.

Medicines are sometimes prescribed for conditions that are not described in patient information leaflets.This medicine is for

your use only.Never give it to other people.Do not use Baycol for a condition for which it was not prescribed.Ask your doctor

if you have any questions.You can ask your doctor or pharmacist for information about Baycol that was written for health care

professionals.

FORTOVASE  (saquinavir)

[November 13, 2000

Hoffman-La Roche]

 INVIRASE (saquiniavir mesylate)

[November 14, 2000

Hoffman-La Roche]

[Invirase]

WARNINGS:

New second paragraph added - 

Concomitant use of INVIRASE with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including INVIRASE, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin, or cerivastatin). Since increased concentrations of statins can, in rare cases, cause severe adverse events such as myopathy including rhabdomyolysis, this risk may be increased when HIV protease inhibitors, including saquinavir, are used in combination with these drugs.

New first paragraph added - 

 INVIRASE (saquinavir mesylate) capsules and FORTOVASE (saquinavir) soft gelatin capsules are not bioequivalent and cannot be used interchangeably. Only FORTOVASE should be used for the initiation of saquinavir therapy (see DOSAGE AND ADMINISTRATION) since FORTOVASE soft gelatin capsules provide greater bioavailability and efficacy than INVIRASE capsules. For patients taking INVIRASE capsules with a viral load below the limit of quantification, a switch to FORTOVASE is recommended to maintain a virologic response. For patients taking INVIRASE capsules who have not had an adequate response or are failing therapy, if saquinavir resistance is clinically suspected, then FORTOVASE should not be used. If resistance to saquinavir is not clinically suspected, a switch to FORTOVASE may be considered.

[Fortovase]

WARNINGS:

New second paragraph added - 

Concomitant use of FORTOVASE with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including FORTOVASE,are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin, or cerivastatin). Since increased concentrations of statins can, in rare cases, cause severe adverse events such as myopathy including rhabdomyolysis, this risk may be increased when HIV protease inhibitors, including saquinavir, are used in combination with these drugs.

PRECAUTIONS: General:

New first paragraph added - 

 FORTOVASE (saquinavir)soft gelatin capsules and INVIRASE (saquinavir mesylate)capsules are not bioequivalent and cannot be used interchangeably. Only FORTOVASE should be used for the initiation of saquinavir therapy (see DOSAGE AND ADMINISTRATION )since FORTOVASE soft gelatin capsules provide greater bioavailability and efficacy than INVIRASE capsules. For patients taking INVIRASE capsules with a viral load below the limit of quantification, a switch to FORTOVASE is recommended to maintain a virologic response.For patients taking INVIRASE capsules who have not had an adequate response or are failing therapy, if saquinavir resistance is clinically suspected, then FORTOVASE should not be used. If resistance to saquinavir is not clinically suspected, a switch to FORTOVASE may be considered.

[Fortovase & Invirase]

New paragraph added to end of subsection - 

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

[Fortovase & Invirase]

Drug Interactions:

New subsection added - 

Sildenafil: In a study performed in healthy male volunteers, coadministration of saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C max and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. When sildenafil is administered concomitantly with saquinavir a starting dose of 25 mg of sildenafil should be considered.

[Fortovase]

Pregnancy:

New paragraph added - 

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including FORTOVASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Text revised with revisions incorporated below -

 The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving antiretroviral medications, including FORTOVASE.

[Invirase]

Pregnancy:

New paragraph added - 

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including INVIRASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Text revised with revisions incorporated below -

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving antiretroviral medications, including INVIRASE.

[Fortovase]

Geriatric Use:

Text revised with revisions incorporated below - 

Clinical studies of FORTOVASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.In general,caution should be taken when dosing FORTOVASE in elderly patients due to the greater frequency of decreased hepatic,renal,or cardiac function,and of concomitant disease or other drug therapy.

[Invirase]

Text revised with revisions incorporated below - 

Clinical studies of INVIRASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be taken when dosing INVIRASE in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

[Fortovase]

New first paragraph added - 

FORTOVASE (saquinavir) soft gelatin capsules and INVIRASE (saquinavir mesylate) capsules are not bioequivalent and cannot be used interchangeably. When using saquinavir as part of an antiviral regimen FORTOVASE is the recommended formulation. In rare circumstances, INVIRASE may be considered if it is to be combined with antiretrovirals that significantly inhibit saquinavir ’s metabolism (see CLINICAL PHARMACOLOGY: DRUG INTERACTIONS ).

[Invirase]

New first paragraph added - 

INVIRASE (saquinavir mesylate) capsules and FORTOVASE (saquinavir) soft gelatin capsules are not bioequivalent and cannot be used interchangeably. When using saquinavir as part of an antiviral regimen FORTOVASE is the recommended formulation. In rare circumstances, INVIRASE may be considered if it is to be combined with antiretrovirals that significantly inhibit saquinavir's metabolism (see CLINICAL PHARMACOLOGY: DRUG INTERACTIONS).

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Lactated Ringer's Injection

Lactated Ringer's and 5% Dextrose Injection

M/6 Sodium Lactate Injection

Ringer's Injection

Ringer's and 5% Dextrose Injection

[November 2, 2000: Baxter Healthcare]

To the PRECAUTIONS section for the above submissions the following Geriatric Use
subsection has been added as the fifth paragraph as follows:

Geriatric Use:
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose section 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 drug therapy.

For Ringer's and 5% Dextrose Injection and Lactated Ringer's and 5% Dextrose Injection, the following revisions have been made:

Under the DESCRIPTION section, paragraph 3, line 4 and 5 which reads,
" Solutions in contact . . . per million. However, the . . . toxicity studies."
has been replaced with the following:
"Solutions in contact with the plastic container may leach out certain chemical
components from the plastic in very small amounts; however, biological testing was
supportive of the safety of the plastic container materials."

For Ringers's and 5% Dextrose Injection, USP the following revision has
been made:

Under the CONTRAINDICATIONS section, the sentence "None known" has been
revised to read:
"Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products."

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Lovenox (enoxaparin sodium)
 [November 17, 2000: Aventis Pharmaceuticals Products]

[Other labeling changes not appearing in 2000 PDR: May 2000 ]

[Other labeling changes not appearing in 2000 PDR: August 2000 ]

This supplemental new drug application provides for the use of Lovenox (enoxaparin sodium)
Injection for the thromboprophylaxis of deep vein thrombosis, which may lead to pulmonary embolism,
in medical patients who are at risk for thromboembolic complications due to severely restricted mobility
during acute illness.

Additional labeling changes - 

WARNINGS:

(New text in bolded italics) - 

Cases of epidural or spinal hematomas have been reported with the associated use of enoxaparin and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs (see boxed WARNING; ADVERSE REACTIONS, Ongoing Safety Surveillance; and PRECAUTIONS, Drug Interactions).

Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal.

Bleeding can occur at any site during therapy with enoxaparin. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

Thrombocytopenia: Thrombocytopenia can occur with the administration of Lovenox Injection.

Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given Lovenox Injection, 1.2% in patients given heparin, and 0. 7% ["0.6%" deleted] in patients given placebo in clinical trials.

Platelet counts less than 50,000/mm 3 occurred at a rate of 0.1% in patients given Lovenox Injection, in 0.2% of patients given heparin, and 0.4% ["0%" deleted] of patients given placebo in the same trials.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3 , enoxaparin should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death.

ADVERSE REACTIONS: 

(New text in bolded italics) - 

Ongoing Safety Surveillance: Since 1993, there have been more than 68 ["60" deleted] reports of epidural or spinal hematoma formation with concurrent use of enoxaparin and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Other Ongoing Safety Surveillance Reports: local reactions at the injection site (i.e., skin necrosis, nodules,inflammation, oozing), systemic allergic reactions (i.e., pruritus, urticaria, anaphylactoid reactions), vesiculobullous rash, purpura, thrombocytosis, and thrombocytopenia with thrombosis (see WARNINGS, Thrombocytopenia). Very rare cases of hyperlipidemia have been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.

DOSAGE AND ADMINISTRATION:

New subsection:

Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely

restricted mobility during acute illness, the recommended dose of Lovenox Injection in 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Lovenox injection has been well

tolerated in the controlled clinical trial.

(New text in bolded italics) - 

Administration: Enoxaparin injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

When using Lovenox Injection ampules, to assure withdrawal of the appropriate volume of drug, the use of a tuberculin

syringe or equivalent is recommended.

Lovenox Injection is administered by SC injection. It must not be administered by intramuscular injection. Lovenox

Injection is intended for use under the guidance of a physician. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided. 

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Methotrexate Sodium

Tablets & Injection

[November 8, 2000: Lederle]

CLINICAL PHARMACOLOGY:

The following paragraph added:

In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m² provided significant clinical improvement compared to placebo as measured by either the physician's global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m²/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m² was not significantly more effective than placebo in this trial.

Pharmacokinetics:

The following changes are given for this subsection:

The following sentence is changed from, "In leukemic pediatric patients, oral absorption has been reported to vary widely (23% to 95%)", to "In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%)."

The following sentence concerning leukemic pediatric patients is added. "The absorption of doses greater than 40 mg/m² has been reported to be significantly less than that of lower doses."

The following sentence is added. "As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m²/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours."

The following sentence is added. "In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m²) or for JRA (3.75 to 26.2 mg/m²), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively."

INDICATIONS AND USAGE: 

Rheumatoid Arthritis:  

The section modified as follows:

Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis

Methotrexate is indicated in the management of selected adults with severe, active, rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full-dose non-steroidal anti-inflammatory agents (NSAIDs).

Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs, including salicylates has not been fully explored (See PRECAUTIONS, Drug Interactions.) Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.

PRECAUTIONS:  

Pediatric Use:

The following is added:

Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.

Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)

 ADVERSE REACTIONS: 

Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies: modified as follows:

The appropriate incidences of methotrexate…..........pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5mg-15mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.)

Other less common reactions included .…….. and vaginal discharge.

Adverse Reactions in JRA Studies:

The following subsection and paragraph is added

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m²/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m²/wk in JRA, the published data for doses above 20 mg/m²/wk are too limited to provide reliable estimates of adverse reaction rates.

 DOSAGE AND ADMINISTRATION: 

 the following subsection is added:

Juvenile Rheumatoid Arthritis: Methotrexate doses reported in published clinical studies of pediatric patients with JRA have ranged from 4 to 17 mg/m²/week or 0.1 to 1.1 mg/kg/week. The duration of methotrexate therapy in these studies ranged from 1 month to 7.3 years. In the majority of these studies, methotrexate was administered orally; however, in some instances methotrexate was administered intramuscularly.

Regarding the proposed addition above, the following changes were made to the existing text:

Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules

1. Single oral doses of 7.5 mg once weekly.

2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.

Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m² given once weekly.

For either adult RA or polyarticular-course JRA dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m²/wk in children, there are too few published data to assess how doses over 20 mg/m²/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m²/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

Naropin (ropivacaine HCl) Injection.
 [November 2, 2000: AstraZeneca]


This supplemental new drug application provides for increasing dosage for nerve block
anesthesia using Naropin 7.5mg/mL and for extending the duration of treatment for
postoperative analgesia using Naropin 2mg/mL. Contact the company for a copy of the package insert.

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Navelbine (vinorelbine tartrate) Injection

 [November 29, 2000: Glaxo Wellcome]

 [Other labeling changes not appearing in 2000 PDR: May 2000 ]

 [Other labeling changes not appearing in 2000 PDR: June 2000 ]

ADVERSE REACTIONS:

Observed During Clinical Practice:

Gastrointestinal:  "pancreatitis" added

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Prevacid (lansoprazole) Delayed-Release Capsules
 [November 30, 2000: TAP Pharmaceutical Products]

 [Other labeling changes not appearing in 2000 PDR: June 2000 ]

This supplemental new drug application provides for the use of Prevacid (lansoprazole) Delayed-Release

Capsules for the following two new indications: 1) for the treatment of NSAID-associated gastric ulcer in

patients who continue NSAID use; and 2) for reducing the risk of NSAID-associated gastric ulcers in

patients with history of a documented gastric ulcer who require the use of a NSAID. Contact the company for a copy of the new labeling/package insert.

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Primacor (milrinone lactate) Injection
[November 29, 2000: Sanofi-Synthelabo]

[Not found in 2000 PDR]

ADVERSE REACTIONS:

Other Effects:

"and in the post-marketing experience, liver function
test abnormalities have been reported"  has been added to the second paragraph.

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PROZAC (fluoxetine HCl) Pulvules

 SERAFEM (fluoxetine HCl) Pulvules

 [November 28, 2000: Eli Lilly]

DESCRIPTION:

New text in bolded italics:

Prozac (fluoxetine hydrochloride) is an antidepressant for oral administration; it is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem , fluoxetine hydrochloride).

CONTRAINDICATIONS:

New text added to end of section:

Thioridazine—Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS).

WARNINGS:
New text (in bolded italics) added to end of section:

Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur

in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued.

New last paragraph:

For Serafem labeling -

Female Sexual Dysfunction with SSRIs—Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a mood-related disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (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. For example, in women (age 18-45) receiving fluoxetine for indications other than PMDD, decreased libido was seen at an incidence of 4% for fluoxetine compared to 1% for placebo. There have been spontaneous reports in women (age 18-45) taking fluoxetine for indications other than PMDD of orgasmic dysfunction, including anorgasmia.

Associated with Discontinuation in US Placebo-Controlled Clinical Trials (excluding data from extensions of trials) -  

Text added at end of subsection -

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. In patients enrolled in US depression, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine 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.

Other Events Observed In All US Clinical Trials-

Text added to end of subsection -

*Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome.
[Referring to the Body as a Whole subsection]

Postintroduction Reports-

Revised text (in bolded italics) -

Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors.

OVERDOSAGE:

Section substantially revised and replaced with the following:

Human Experience—Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.

 Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all six overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal.

Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope.

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Sustiva (efavirenz) Capsules

 [November 14, 2000: DuPont Pharmaceuticals]

 [Other labeling changes not appearing in 2000 PDR: February 2000 ]

This supplemental new drug application provides for new safety information and consistency among the
antiretroviral labels with regards to the Antiretroviral Pregnancy Registry and Nursing Mothers
subsections of the package insert. The following changes have been made to the Information for
Patients, Nursing Mothers subsection under the PRECAUTIONS section of the Sustiva labeling:

Nursing Mothers:
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed
their infants to avoid risking postnatal transmission of HIV. Although it is not known if efavirenz is
secreted in human milk, efavirenz is secreted into the milk of lactating rats. Because of the potential for
HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be
instructed not to breast-feed if they are receiving SUSTIVA.

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TALACEN (pentazocine/acetaminophen) Tablets

 [November 1, 2000: Sanofi-Synthelabo]

ADVERSE REACTIONS: 

Other:

The following events were added:

"...serious skin reactions, including erythema multiforme, Stevens-Johnson Syndrome...

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Tamiflu (oseltamivir phosphate) Capsules
[November 17, 2000: Hoffmann-La Roche]

This supplemental new drug application provides for the use of Tamiflu (oseltamivir phosphate) 75 mg
for the prophylaxis of influenza virus in adults and adolescents 13 years and older. Contact the company for a copy of the new labeling/package insert or go to the following link and look for Tamiflu:

http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_november_2000.html

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Viramune (nevirapine) Tablets and Oral Suspension  

 [Other labeling changes not appearing in 2000 PDR: August 2000 ]

Labeling changes, some extensive, to BLACK BOX WARNING, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections. For the new label and safety alert, click on the following link:  

http://www.fda.gov/medwatch/safety/2000/safety00.htm#viramu

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Zithromax (azithromycin) Capsules, Single Dose Packet and Tablets
 [November 13, 2000: Pfizer]

These supplemental new drug applications provide for revision to the combined package insert for the
use of Zithromax Tablets, 600 mg, in combination with ethambutol, for the treatment of disseminated
Mycobacterium avium complex (MAC) infections in persons with advanced HIV infection. Contact the

company for a copy of the new labeling/package insert.

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ZOCOR (simvastatin) Tablets

[November 7, 2000: Merck]

[Other labeling changes not appearing in 2000 PDR:  April 2000 ]

[Other labeling changes not appearing in 2000 PDR: August 2000 ]

CLINICAL PHARMACOLOGY:

Pharmacokinetics: New next to last paragraph added - 

In a study including 16 elderly patients between 70 and 78 years of age who received Zocor 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients (see PRECAUTIONS, Geriatric Use)

Clinical Studies: New last paragraph added - 

Additionally, in this study, 1,021 of the patients were 65 and older. Cholesterol reduction with simvastatin resulted in similar decreases in relative risk for total mortality, and major coronary events in these elderly patients, compared with younger patients.

PRECAUTIONS:

Geriatric Use: New subsection - 

A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S and other large clinical studies conducted with simvastatin, 22% of patients were elderly (1,522 of 6,985 patients were greater than or equal to 65 years). Simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD (see CLINICAL PHARMACOLOGY). Lipid-lowering efficacy was at least as great in elderly patients compared  with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range.

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Zoloft (sertraline HCl) Tablet

 [November 16, 2000: Pfizer] 

ADVERSE REACTIONS:

(New text in bold italics)

Other Events Observed During the Postmarketing Evaluation of ZOLOFT - Reports of adverse events temporally associated with ZOLOFT that have been received since market introduction, that are not listed above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, ["priapism" deleted] , galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events - clinical features (which in the majority of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.

OVERDOSAGE:
Section extensively revised. Revisions incorporated below:

Human Experience – Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).

Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in

fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone

and subsequently recovered. However, another patient who took 2.5 grams of sertraline

hydrochloride alone experienced a fatal outcome.

Other important adverse events reported with sertraline hydrochloride overdose (single or

multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium,

hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.

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ZYBAN (bupropion HCl) Tablets

[November 28, 2000: Glaxo Wellcome]

CLINICAL PHARMACOLOGY:

Clinical Trials:

Addition of third trial with accompanying revisions: [Not in 2000 PDR]

In this study, patients treated with any of the three treatments achieved greater 4- week abstinence rates than patients treated with placebo.

Table 2 presents quit rates over time by treatment group for the comparative trial.

When patients in this study were followed out to one year, the superiority of ZYBAN and the combination of ZYBAN and NTS over placebo in helping patients to achieve abstinence from smoking was maintained. The continuous abstinence rate was 30% (95% Cl 24-35) in the ZYBAN treated patients, and 33% (95% Cl 27-39) for patients treated with the combination at 26 weeks compared with 13% (95% Cl 7-18) in the placebo group. At 52 weeks, the continuous abstinence rate was 23% (95% Cl 18-28) in the ZYBAN treated patients, and 28% (95% Cl 23-34) for patients treated with the combination, compared with 8% (95% Cl 3-12) in the placebo group. Although the treatment combination of ZYBAN and NTS displayed the highest rates of continuous abstinence throughout the study, the quit rates for the combination were not significantly higher ( P >0.05) than for ZYBAN alone.

The comparisons between ZYBAN, NTS, and combination treatment in this study have not been replicated, and, therefore should not be interpreted as demonstrating the superiority of any of the active treatment arms over any other.

The third study was a long-term maintenance trial conducted at five clinical centers. Patients in this study received open-label ZYBAN 300 mg/day for 7 weeks. Patients who quit smoking while receiving ZYBAN (n = 432) were then randomized to ZYBAN 300 mg/day or placebo for a total study duration of 1 year. Abstinence from smoking was determined by patient self-report and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months, continuous abstinence rates were significantly higher for patients continuing to receive ZYBAN than for those switched to placebo ( P <0.05; 55% versus 44%).

Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates. Quit rates for ZYBAN were similar in patients with and without prior quit attempts using nicotine replacement therapy.

PRECAUTIONS:

General: Allergic Reactions:

New paragraph added to end of subsection - [Not in 2000 PDR] 

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

Use In Patients With Systemic Illness: 

Reorganized with some revisions regarding NTS into:

Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.

Data from a comparative study of ZYBAN, nicotine transdermal system (NTS), the combination of sustained release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment- emergent hypertension in patients treated with the combination of ZYBAN and NTS. In this study, 6.1% of patients treated with the combination of ZYBAN and NTS had treatment- emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with ZYBAN, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1. 2%) treated with the combination of ZYBAN and NTS and one patient (0. 4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

There is no clinical experience establishing the safety of ZYBAN in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in two patients for exacerbation of baseline hypertension

Renal or Hepatic Impairment: Because bupropion hydrochloride and its metabolites are almost completely excreted through the kidney and metabolites are likely to undergo conjugation in the liver prior to urinary excretion, treatment of patients with renal or hepatic impairment should be initiated at reduced dosage as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible toxic effects of elevated blood and tissue levels of drug and metabolites.

Drug Interactions:

New text added to second paragraph - [Not in 2000 PDR] 

The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg ZYBAN tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and its hydroxy metabolite were unaffected. However, there were 16% and 32% increases, respectively, in the AUC and C max of the combined moieties of theohydro- and erythrohydro bupropion

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[Other labeling changes not appearing in 2000 PDR: March 2000 ]

This supplemental new drug application provides for the use of Zyprexa (olanzapine) for the
maintenance of treatment response. Contact the company for the complete labeling/package insert.

The effectiveness of Zyprexa in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Zyprexa for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Replaced with the following:

months has been demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY).

the long-term usefulness of the drug for the individual patient (see DOSAGE AND

DOSAGE AND ADMINISTRATION:

New text regarding new indication:

been demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY). Patients should

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