![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20090118022506im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: October 13, 2000)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
NB: Comparison made to 2000 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
|
(disulfiram) |
(mesalamine) |
(sulfasalazine) |
(ciprofloxacin HCl) |
(dorzolamide HCl/timolol maleate) |
(dalteparin sodium) |
(somatropin) |
(ammonium lactate) |
(etodolac) |
(alosetron HCl) |
(enoxaparin sodium) |
(fluvoxamine maleate) |
(lovastatin) |
(nimodipine) |
(vecuronium bromide) |
(somatropin) |
(somatropin) |
(felodipine) |
(mirtazapine) |
(tretinoin) |
(ceftriaxone sodium) |
(nevirapine) |
(vinblastine sulfate) |
(estradiol) |
(simvastatin) |
"Hepatic toxicity including hepatic failure resulting in transplantation or death have been reported. Severe and sometimes fatal hepatitis associated with disulfiram therapy may develop even after many months of therapy. Hepatic toxicity has occurred in patients with or without prior history of abnormal liver function. Patients should be advised to immediately notify their physician of any early symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice or dark urine."
Fifth paragraph revised (new text in italics) -
"Baseline and follow-up ["transaminase tests" deleted] liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with Antabuse therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.["a sequential multiple analysis (SMA 12) test should be made every six months." deleted]
"Multiple cases of hepatitis, including both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in transplantation or death, have been reported with administration of Antabuse."
"Clinical studies of Asacol 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, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Asacol. Reports from uncontrolled clinical studies and post-marketing reporting systems suggest a higher incidence of blood dyscrasias, i.e., agranolocytosis, neutropenia, pancytopenia, in subjects receiving Asacol who are 65 years or older. Caution should be taken to closely monitor blood cell counts during 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 when prescribing this drug therapy. As stated in the PRECAUTIONS section, it is recommended that all patients have an evaluation of renal function prior to initiation of Asacol tablets and periodically while on Asacol therapy."
Gastrointestinal: [replaces "Digestive:" title heading] New information on hepatotoxicity added to subsection -
"There have been rare reports of hepatotoxicity including, jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. Asymptomatic elevations of liver enzymes which usually resolve during continued use or with discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome which included changes in liver enzymes was reported."
Respiratory/Pulmonary: adverse event added: "pleuritis".
[Other labeling changes not appearing in 2000 PDR: Apr00]
[Other labeling changes not appearing in 2000 PDR: Jun00
"Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate."
Geriatric Use: Subsection added -
"No overall differences in safety or effectiveness have been observed between elderly and younger patients."
"Signs and symptoms of local reactions including palpebral reactions and systemic reactions including angioedema, bronchospasm, pruritus, urticaria;"
[Other labeling changes not appearing in 2000 PDR: Jun00]
"The safety and effectiveness of Genotropin in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of Genotropin and may be more prone to develop adverse reactions."
[Other labeling changes not appearing in 2000 PDR: Letter
[Other labeling changes not appearing in 2000 PDR: May00]
"In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for enoxaparin versus heparin (32.0% vs. 35.7%)."
"Co-administration of thioridazine, terfenadine, astemizole, cisapride or pimozide with Luvox Tablets is contraindicated (see WARNINGS and PRECAUTIONS)."
"The effect of fluvoxamine (25 mg bid for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased threefold following coadministration of fluvoxamine.
"Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses.
"Therefore, fluvoxamine and thioriadzine should not be co-administered (see CONTRAINDICATIONS and PRECAUTIONS). "
"Thioridazine: See CONTRAINDICATIONS and WARNINGS."
"Worldwide exposure to fluvoxamine maleate includes over 45,000 patients treated in clinical trials and an estimated exposure of 23,000,000 patients treated during worldwide marketing experience (circa 1999). Of the 462 cases of deliberate or accidental overdose involving fluvoxamine maleate reported from this population, there were 44 deaths. Of these, six were in patients taking fluvoxamine maleate alone and the remaining 38 were in patients taking fluvoxamine maleate with other drugs. Among non-fatal overdose cases, 373 patients had complete recovery; four patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, kidney complications (from trauma associated with overdose), and bowel infarction requiring a hemicolectomy. In the remaining 41 patients, the outcome was unknown. The largest known ingestion of fluvoxamine maleate involved 12,000 mg (equivalent to 2 to 3 months' dosage). The patient fully recovered. However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.
"Commonly (greater than or equal to 5%) observed adverse events associated with fluvoxamine maleate overdose include coma, hypokalemia, hypotension, nausea, respiratory difficulties, somnolence, tachycardia and vomiting. Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include, bradycardia, ECG abnormalities, (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, tremor, diarrhea, and increased reflexes. "
"Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its beta-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold, respectively [as measured using a chemical assay - high performance liquid chromatography]. In a second study, 15 subjects consumed one 8 oz. glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its beta-hydroxacid metabolite [measured using a chemical assay - liquid chromatography/tandem mass spectrometry - different from that used in the first** study] of 1.94-fold and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. "
Last paragraph, fourth sentence revised (new text in italics) -
"These include cyclosporine; the azole antifungals, itraconazole and ketoconazole; the macrolide antibiotics, erythromycin and clarithromycin; HIV protease inhibitors; the antidepressant nefazodone; and large quantities of grapefruit juice (>1 quart daily)(see below; CLINICAL PHARMACOLOGY Pharmacokinetics; PRECAUTIONS, Drug Interactions; and DOSAGE AND ADMINISTRATION)."
Reducing the risk of myopathy.
2. Measures to reduce the risk of myopathy caused by drug interactions (see above and PRECAUTIONS, Drug Interactions).
Last paragraph revised (new text in italics) -
In patients taking concomitant cyclosporine, fibrates or niacin, the dose of lovastatin should generally not exceed 20 mg/day (see DOSAGE AND ADMINISTRATION and DOSAGE AND ADMINISTRATION, Concomitant Lipid-Lowering Therapy), as the risk of myopathy increases substantially at higher doses. ["Interruption of lovastatin therapy during a course of treatment with a systemic antifungal azole or a macrolide antibiotic should be considered" deleted] Concomitant use of lovastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) is not recommended. If no alternative to a short course of treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is available, a brief suspension of lovastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
Two subsections added -
"Gemfibrozil and other fibrates, lipid-lowering doses (greater than or equal to 1 g/day) of niacin (nicotinic acid):
These drugs increase the risk of myopathy when concomitantly with lovastatin, probably because they can produce myopathy when given alone (see WARNINGS, Skeletal Muscle). There is no evidence to suggest that these agents affect the pharmacokinetics of lovastatin.
"CYP3A4 Interactions: Lovastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. However, lovastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the plasma concentration of HMG-CoA reductase inhibitory activity during lovastatin therapy. These inhibitors include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, and large quantities of grapefruit juice (>1 quart daily) (see CLINICAL PHARMACLOLGY, Pharmacokinetics and WARNINGS, Skeletal Muscle).
"Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. Large quantities of grapefruit juice (>1 quart daily) significantly increase the serum concentrations of lovastatin and its beta-hydroxyacid metabolite during lovastatin therapy and should be avoided (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Skeletal Muscle)."
[Other labeling changes not appearing in 2000 PDR: Dec00]
"The use of Norcuran (vecuronium bromide) for injection in patients undergoing cesarean section has been reported in the literature. Following tracheal intubation with succinylcholine, Norcuran dosages of 0.04 mg/kg (n=11) and 0.06 to 0.08 mg/kg (n=20) were administered. The umbilical venous plasma concentrations were 11% of maternal concentrations at delivery and mean neonate APGAR scores at 5 minutes were greater than or equal to 9 in both reports. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy."
Nursing Mothers: Subsection added -
"It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Norcuran (vecuronium bromide) for Injection is administered to a nursing woman."
"Norditropin should not be used or should be discontinued when there is any evidence of active malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to the institution of growth hormone therapy."
"Progression of scoliosis can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis. "
"Fluid retention and peripheral edema may occur."
[Changes not appearing in 2000 PDR: Apr00, Nov99, Dec99]
[Changes not in 1999 PDR]
"Growth hormone should not be initiated to treat patients with acute critical illnesses due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone-deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS).""
"See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who currently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illness should be weighed against the potential risk."
"Clinical studies of Nutropin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects, Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
[Other labeling changes not appearing in 2000 PDR: Feb00]
First paragraph, first and second sentences; third paragraph, first sentence - the phrase "28 times**" was recalculated to "61 times**".
Third paragraph - the phrase "28 times**" was recalculated to "61 times**"
Fourth paragraph - the phrase "506 times**" was recalculated to "1100 times**"
Last paragraph revised (new text in italics) -
"A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 , mg/kg/day (up to 24 times ** the maximum recommended human dose on a mg/m² basis.) showed no significant effect of felodipine on reproductive performance."
PREGNANCY
Pregnancy Category C
Teratogenic effects - first paragraph, first sentence - "from 0.4 to 4 times**" was recalculated to "0.5 to 5 times**".
Nonteratogenic effects - first paragraph, first sentence - "4 times**" was recalculated to "8 times**".
Second paragraph, first sentence revised (new text in italics) -
"Significant enlargement of the mammary glands, in excess of the normal enlargement for normal rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (["equal to" deleted] 2.1 times the maximum human dose on a mg/m² basis)."
"Clinical studies of felodipine 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. Pharmacokinetics, however, indicate that the availability is increased in older patients(see CLINICAL PHARMACOLOGY), Geriatric use). 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. "
"Geriatric Use - Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine (see CLINICAL PHARMACOLOGY). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients should have their blood pressure closely monitored during any dosage adjustment.
"Patients with Impaired Liver Function - Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of Plendil; therefore, patients should have their blood pressure monitored closely during dosage adjustment of Plendil (see CLINICAL PHARMACOLOGY). "
"Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
"Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion or exchange transfusion in the treatment of mirtazapine overdosage. No specific antidotes for mirtazapine are known."
Second paragraph, last sentence added -
"Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR)."
"Ceftriaxone crosses the blood placenta barrier."
Microbiology: First paragraph, last sentence deleted - "Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see INDICATIONS AND USAGE)."
Replaced with -
"Ceftriaxone has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section."
Last paragraph deleted - "Ceftriaxone also demonstrates in vitro activity against most strains of the following microorganisms, although the clinical significance is unknown."
Replaced with -
"The following in vitro data are available, but their clinical significance is unknown. Ceftriaxone exhibits in vitro minimal inhibitory concentrations (MICs) of less than or equal to 8 µ g/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of ceftriaxone in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Susceptibility Tests: This subsection has been extensively revised. To see the revised subsection contact the company for a copy of the new labeling/package insert.
"The incidence of warmth, tightness or induration ["injection site reaction" deleted] was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL"
Last paragraph revised (new text in italics) -
"Other rarely observed adverse reactions (< 0.1%) include leukocytosis, lymphocytosis, monocytosis, basophilia, a decrease in the prothrombin time, jaundice, gallbladder sludge, glycosuria, hematuria, anaphylaxis, bronchospasm, serum sickness, abdominal pain, colitis, flatulence, dyspepsia, palpitations, epistaxis, biliary lithiasis, agranulocytosis, renal precipitations, and nephrolithiasis.
"In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic."
"Withdraw entire contents of vial into syringe to equal total labeled dose ["approximately 1.4 mL" from first paragraph and "approximately 2.8 mL" from second pargraph deleted]."
COMPATIBILITY AND STABILITY: New sixth and seventh paragraphs -
"Ceftriaxone has been shown to be compatible with Flagyl IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidzole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl IV RTU (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.
"Vancomycin and fluconazole are physically incompatible with ceftriaxone in admixtures. When either of these drugs is to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations."
New ninth paragraph -
"Note: Parenteral drug products should be inspected visually for particulate matter before administration."
"It is extremely important that the intravenous needle or catheter be properly positioned before any Velban is injected. Leakage into surrounding tissue during intravenous administration of Velban may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein."
"Syringes containing this product should be labeled, using the auxiliary sticker provided, to state 'FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY.'"
The paragraphs referring to inadvertent intrathecal administration of vinca alkaloids revised with revisions incorporated below -
"After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.
"There are no published cases of survival following intrathecal administration of Velban to base treatment on. However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate 1-3, if Velban is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:
1. Removal of as much CSF as is safely possible through the lumbar access.
2. Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer's solution. Fresh frozen plasma should be requested and, when available, 25 mL should be added to every 1 liter of lactated Ringer's solution.
3. Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer's solution should be given by continuous infusion at 150 mL/hour, or at a rate of 75 mL/hour when fresh frozen plasma has been added as above.
"The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dL.
"The following measures have also been used in addition but may not be essential:
Glutamic acid, 10 grams, has been given intravenously over 24 hours, followed by 500 mg three times daily by mouth for 1 month. Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/hour for 24 hours, then bolus doses of 25 mg every 6 hours for 1 week. Pyridoxine has been given at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.
"This preparation is for intravenous use only (see WARNINGS).
"Special Dispensing information - WHEN DISPENSING VELBAN IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: "DO NOT REMOVE COVERING UNTIL THE MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY."(see Warnings). A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: "FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY".
"Caution - It is extremely important that the intravenous needle or catheter be properly positioned before any Velban is injected. Leakage into surrounding tissue during intravenous administration of Velban may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis."
"Concomitant use of St. John's wort (hypericum perforatum) or St. John's wort containing products and Viramune is not recommended. Coadministration of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), including Viramune, with St. John's wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of Viramune and lead to loss of virologic response and possible resistance to Viramune or to the class of NNRTIs. "
"Viramune may interact with some drugs, therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort."
[Other labeling changes not appearing in 2000 PDR: Feb00]
[Other labeling changes not appearing in 2000 PDR: Apr00, Nov99]
"In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
"Simvastatin is a substrate for CYP3A4 (see PRECAUTIONS, Drug Interactions). " Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice resulted mean increases in the concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 2.4-fold and 3.6-fold, respectively, and of simvastatin and its beta-hydroxyacid metabolite [measured using a chemical assay - liquid chromatography/tandem mass spectrometry] of 16-fold and 7-fold, respectively. In a second study, 16 subjects consumed one 8 oz. glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first** study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.13-fold and 1.18-fold, respectively, and of simvastatin and its beta-hydroxacid metabolite [measured using a chemical assay - liquid chromatography/tandem mass spectrometry] of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied."
Second paragraph, fourth sentence revised (new text in italics) -
"These include cyclosporine; the azole antifungals, itraconazole and ketoconazole; the macrolide antibiotics, erythromycin and clarithromycin; HIV protease inhibitors; the antidepressant nefazodone; and large quantities of grapefruit juice (>1 quart daily)(see below; CLINICAL PHARMACOLOGY Pharmacokinetics; PRECAUTIONS, Drug Interactions; and DOSAGE AND ADMINISTRATION)."
Reducing the risk of myopathy.
2. Measures to reduce the risk of myopathy caused by drug interactions (see above and PRECAUTIONS, Drug Interactions).
Last paragraph revised (new text in italics) -
In patients taking concomitant cyclosporine, fibrates or niacin, the dose of simvastatin should generally no exceed 20 mg/day (see DOSAGE AND ADMINISTRATION and DOSAGE AND ADMINISTRATION, Concomitant Lipid-Lowering Therapy), as the risk of myopathy increases substantially at higher doses. ["Interruption of simvastatin therapy during a course of treatment with a systemic antifungal azole or a macrolide antibiotic should be considered" deleted] Concomitant use of simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) is not recommended. If no alternative to a short course of treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is available, a brief suspension of simvastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
Two subsections added -
"Gemfibrozil and other fibrates, lipid-lowering doses (greater than or equal to 1 g/day) of niacin (nicotinic acid):
These drugs increase the risk of myopathy when concomitantly with simvastatin, probably because they can produce myopathy when given alone (see WARNINGS, Skeletal Muscle). There is no evidence to suggest that these agents affect the pharmacokinetics of simvastatin.
"CYP3A4 Interactions: Simvastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. However, simvastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the plasma concentration of HMG-CoA reductase inhibitory activity during simvastatin therapy. These inhibitors include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, and large quantities of grapefruit juice (>1 quart daily) (see CLINICAL PHARMACLOLGY, Pharmacokinetics and WARNINGS, Skeletal Muscle).
"Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. Large quantities of grapefruit juice (>1 quart daily) significantly increase the serum concentrations of simvastatin and its beta-hydroxyacid metabolite during simvastatin therapy and should be avoided (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Skeletal Muscle)."
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