![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20090118034602im_/http://www.fda.gov/icon/header.gif){kind=icon}
(posted August 23, 2001)
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 2001 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
| AGENERASE (amprenavir) |
ANTAGON (ganirelix acetate) |
AquaMEPHYTON (phytonadione) |
AVAPRO (irbesartan) |
| AVELOX ABC Pack (moxifloxacin) |
BAYCOL (cerivastatin Na) |
BUSPAR (buspirone HCl) |
DOBUTAMINE |
| EFFEXOR & EFFEXOR XR (venlafaxine HCl) |
FLOMAX (tamsulosin HCl) |
INDERIDE & INDERIDE LA (propranolol HCl/hydrochlorothiazide) |
INOmax (nitric oxide) |
| LAMICTAL (lamotrigine) |
LO/OVRAL (norgestrel/ethinyl estradiol & ferrous fumarate) |
LORABID (loracarbef) |
MERETEK UBT Kit (13C-urea) |
| METHOTREXATE |
MOBAN (molindone HCl) |
MYLOTARG (gemtuzumab ozogamycin) |
ORLAAM (levomethadyl acetate HCl) |
| PREVACID (lansoprazole) |
PROTONIX (pantoprazole Na) |
RESCRIPTOR (delavirdine mesylate) |
REVIA (naltrexone HCl) |
| SEREVENT (salmeterol xinafoate) |
SPORANOX (itraconazole) |
TOBRASONE & TOBRAFLEX (tobramycin & fluorometholone acetate) |
VERSED (midazolam HCl) |
| ZANTAC (ranitidine HCl) |
ZOVIRAX (acyclovir) |
[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/safety/2000/dec00.htm#agener ]
The statement "ALERT: Find out about medicines that should not be taken with AGENERASE" was added to the WARNINGS, PRECAUTIONS, patient package insert and container labeling.
A new heading was added to the patient package insert entitled "MEDICINES YOU SHOULD NOT TAKE WITH AGENERASE".
A new heading was added to the patient package insert entitled "Medicines That Require Dose Adjustments of Special Attention From Your Doctor".
References to pravastatin from the PRECAUTIONS section were removed.
The statement, "ALERT: Find out about medicines that should not be taken with AGENERASE" is in red font inside a red ALERT box on the container labeling. This is followed by the statement, "Note to Pharmacist: Do not cover ALERT box with pharmacy label."
New text in bolded, underlined italics, deletions struck-through -
After initiating FSH therapy on Day 2
or 3 of the cycle, Antagon (ganirelex acetate) Injection 250 µg
may be administered subcutaneously
once daily during the early to mid to late
portion of the follicular phase.
Directions for Using Antagon™ (ganirelex acetate) Injection
5. With syringe held upward, remove needle cover.
Boxed WARNING
Revisions in bolded, underlined italics -
WARNING - INTRAVENOUS AND INTRAMUSCULAR USE
Severe reactions, including fatalities, have occurred during and immediately after INTRAVENOUS injection of AquaMEPHYTON (Phytonadione), even when precautions have been taken to dilute the AquaMEPHYTON and to avoid rapid infusion. Severe reactions, including fatalities, have also been reported following INTRAMUSCULAR administration. Typically these severe reactions have resembled hypersensitivity or anaphylaxis, including shock and cardiac and/or respiratory arrest. Some patients have exhibited these severe reactions on receiving AquaMEPHYTON for the first time. Therefore the INTRAVENOUS and INTRAMUSCULAR routes should be restricted to those situations where the subcutaneous other routes are is not feasible and the serious risk involved is considered justified.
ADVERSE REACTIONS:
Revisions in bolded, underlined italics -
Deaths have occurred after intravenous and intramuscular administration. (See Box Warning )
DOSAGE AND ADMINISTRATION
Whenever possible, AquaMEPHYTON should be given by the subcutaneous ["or intramuscular route" deleted] (See Box Warning).
CLINICAL PHARMACOLOGY:
Special Populations
The following text deleted -
Pediatric: Irbesartan pharmacokinetics have not been investigated in patients <18 years of age.
Replaced with the following text -
The pharmacokinetics of irbesartan were studied in hypertensive children (age 6-12, n=9) and adolescents (age 13-16, n=12) following single and multiple daily doses of 2 mg/kg (maximum dose of 150 mg per day) for 4 weeks. Accumulation with repeated doses was limited (18%) in both age groups. Clearance rates, AUC values, and Cmax values were comparable to adults receiving 150 mg daily. Irbesartan pharmacokinetics have not been investigated in patients <6 years of age.
PRECAUTIONS:
Pediatric Use
Second paragraph added:
Safety and effectiveness in pediatric patients have not been established.
Pharmacokinetic parameters in pediatric subjects (age 6–16, n=21) were comparable to adults. At doses up to 150 mg daily for 4 weeks, AVAPRO (irbesartan) was well tolerated in hypertensive children and adolescents (see CLINICAL PHARMACOLOGY; Special Populations). Blood pressure reductions were comparable to adults receiving 150 mg daily; however, greater sensitivity in some patients cannot be ruled out (See DOSAGE and ADMININSTRATION: Pediatric Patients). AVAPRO has not been studied in pediatric patients less than 6 years old.
DOSAGE and ADMINISTRATION:
Pediatric Patients
Subsection has been added:
Children (< 6 years): safety and effectiveness have not been established.
Children (6-12 years): An initial dose of 75 mg once daily is reasonable. Patients requiring further reduction in blood pressure should be titrated to 150 mg once daily (see PRECAUTIONS; Pediatric Use).
Adolescent patients (13-16 years): An initial dose of 150 mg once daily is reasonable. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily. Higher doses are not recommended (see PRECAUTIONS; Pediatric Use).
[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/apr01.htm#avelox ]
The following "Usual Dosage" statement was added to the spine of the carton: "Usual Dosage: One tablet once daily for 5 days."
The statement "Keep Out of the Reach of Children" was added to the spine of the carton.
The following statement was also added to the bottom of the front of the carton: "This pack is intended only for the treatment of bronchitis. Other
conditions may require a longer duration of therapy."
The statement "Keep Out of the Reach of Children" was added to the spine of the carton.
The following "Usual Dosage" statement was added to the spine of the carton: "Usual Dosage: One tablet once daily for 5 days."
[To view the updated safety information from 08/08/01 on Baycol, click on the following link: http://www.fda.gov/medwatch/safety/2001/safety01.htm#bayco2 ]
CLINICAL PHARMACOLOGY:
Fourth paragraph, deleted text struck-through -
This suggests that food may decrease the extent of presystemic
clearance of buspirone. but the clinical significance of these findings
is unknown.
PRECAUTIONS:
Information for Patients:
Addition of points number 5. and 6..
5. You should take BuSpar consistently, either always with food or always without food.
6. During your treatment with BuSpar, avoid drinking large amounts of grapefruit juice.
Drug Interactions:
New subsection added -
Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)
Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following:
Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations ( verapamil increased AUC and Cmax of buspirone 3.4 fold while diltiazem increased AUC and Cmax 5.3-fold and 4-fold, respectively.) Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment.
Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in Cmax and 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.
Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3-fold increase in Cmax; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice.
Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma concentrations (13-fold increase in Cmax and 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.
Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5-mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%).
Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect.
Other Inhibitors and Inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dosage adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect.
Other Drugs
Cimetidine: coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2-fold), but had minimal effects on the AUC of buspirone.
The following subsection:
Use in the Elderly:
The safety and efficacy profiles of buspirone in 605 anxious, elderly patients (mean age = 70.8 years) were similar to those in a younger population (mean age = 43.3 years). There were no effects of age on the pharmacokinetics of buspirone.
Replaced with:
Geratric Use:
In one study of 6632 patients who received Buspar for the treatment of anxiety, 605 patients were > 65 years old and 41 were > 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). The review of other spontaneously reported adverse clinical events has not identified differences in reporting between elderly and younger patients, but greater sensitivity of some older patients can not be ruled out.
Precautions:
Geriatric Use:
Subsection added:
Clinical studies of dobutamine injection 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.
Description:
5 th and 6 th sentences of the last paragraph have been changed to:
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.
Labeling provides for a new indication - use of Effexor Tablets and Effexor XR Capsules
for the prevention of recurrence of depression and for the prevention of relapse of depression. Contact the company for a copy of the new labeling/package insert.
[Information not found in 2000 PDR]
WARNINGS:
The following text added:
Rarely (probably less than one in fifty thousand patients), tamsulosin, like other alpha 1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition (see Precautions: Information for Patients).
PRECAUTIONS:
The following text added:
Patients should be advised about the possibility of priapism as a result of treatment with FLOMAX Capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence).
ADVERSE REACTIONS:
Post-Marketing Experience:
New text in bolded, underlined italics -
Post-Marketing Experience - Allergic-type reactions such as skin rash, pruritus, angioedema of tongue, lips and face and urticaria have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of palpitations, constipation and vomiting have been received during the post-marketing period.
WARNINGS:
Propranolol Hydrochloride
Diabetes and Hypoglycemia:
1. First paragraph: the phrase "in patients on propranolol" has been added to the end of the last sentence.
2. Second paragraph/Last sentence: "in subjects on propranolol" has been changed to "in patients on propranolol."
3. "Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients on propranolol" has been added to the end of this section.
PRECAUTIONS:
[Inderide LA]
Nursing Mothers
Subsection has been changed from:
"Propranolol and thiazides are excreted in human milk. Caution should be exercised when Inderide LA is administered to nursing women"
To the following:
Nursing Mothers
Propranolol Hydrochloride (Inderal)
"Propranolol is excreted in human breast milk. Caution should be exercised when Inderide LA is administered to a nursing woman."
Hydrochlorothiazide
"Thiazides appear in breast milk. If the use of the drug is deemed essential, the patient should stop nursing.".
Clinical Trials:
New paragraph added -
In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with
pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250 mmHg mmHg despite optimal oxygenation and ventilation, received placebo (N=193) or INOmax (N=192) 5 ppm for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of INOmax on the primary end point of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide(1.25 to 80 ppm). INOmax is not indicated for use in ARDS.
DESCRIPTION
Second sentence has been changed from:
INOmax is a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%).
To the following:
INOmax is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm).
PRECAUTIONS:
Subsection updated to read:
Geriatric
Use: Clinical
studies of Lamictal
did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. In
general, dose
selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant
disease or other drug therapy.
On the back of the blister pack the following text:
"This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases."
Revised to read as follows:
"Take one oral contraceptive (OC) pill every day to best prevent pregnancy. OCs do not prevent AIDS (HIV infection) or other sexually transmitted diseases. See a health care provider for any questions or concerns."
PREACUTIONS:
Geriatric Use subsection revised with revisions in bolded, underlined italics:
Geriatric Use – Healthy geriatric volunteers (>65 years old) with normal renal function who received a single 400-mg dose of loracarbef had no significant differences in AUC or clearance when compared to healthy adult volunteers 20 to 40 years of age (see CLINICAL PHARMACOLOGY). Of 3541 adult patients in controlled clinical studies of loracarbef, 705 (19.9%) were 65 years of age or older. In these controlled clinical studies, when geriatric patients received the usual recommended adult doses, clinical efficacy and safety were comparable to results in non-geriatric patients. Loracarbef 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 significant numbers of elderly patients have decreased renal function, care should be taken in dose selection and evaluation of renal function in this population is recommended (see DOSAGE AND ADMINISTRATION).
Labeling provides for a decrease in dose of 13C-urea from 125 mg to 75 mg in the BreathTek UBT Collection Kit.
INDICATIONS AND USAGE
Neoplastic Diseases
The third paragraph, first sentence will read:
Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma) and lung cancer, particularly squamous cell and small cell types.
DOSAGE AND ADMINISTRATION
Neoplastic Diseases
The Mycosis Fungoides subsection will read:
Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in
advanced stages of the disease.
Labeling changes provide for modification of labeling text to more clearly state that agents in this class are indicated for the treatment of schizophrenia.
Contact the company for a copy of the new labeling/package insert.
[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#mylota ]
Boxed WARNING:
Additional sentences were added to the second paragraph:
There are no controlled trials demonstrating efficacy and safety using Mylotarg in combination with other chemotherapeutic agents. Therefore, Mylotarg should only be used as single agent chemotherapy and not in combination chemotherapy regimens outside clinical trials.
Second paragraph was added:
There are no controlled trials demonstrating efficacy and safety using Mylotarg in combination with other chemotherapeutic agents.
HEPATOTOXICITY subsection of the Boxed WARNING section
The following changes were made with new or moved text in bolded, underlined italics, deletions struck-through:
Hepatotoxicity, including severe hepatic veno-occlusive
disease (VOD), has been reported in
association with the use of Mylotarg as a single agent, as part of a
combination chemotherapy regimen, and in patients
without a history of liver disease or
hematopoietic stem-cell transplant (HSCT). (See WARNINGS
and ADVERSE
REACTIONS sections.)
Patients who receive Mylotarg either before or after HSCT,
patients with underlying hepatic disease or abnormal
liver function, and patients receiving
Mylotarg in combinations with other chemotherapy may be at increased risk
for developing severe VOD. Death from liver failure and from VOD has been
reported in patients who received Mylotarg.
Physicians should monitor their patients carefully
for symptoms of hepatotoxicity, particularly VOD. These symptoms can include:
rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, elevations
in bilirubin and/or liver enzymes. However, careful monitoring may not identify
all patients at risk or prevent the complications of hepatotoxicity.
Patients who receive
Mylotarg either before or after hematopoietic stem-cell transplant (HSCT),
and patients with underlying hepatic disease or abnormal liver function may
be at increased risk for developing severe VOD. Death
from liver failure and from VOD
has been reported in patients who received Mylotarg.
WARNINGS:
First paragraph was revised with additions in bolded, underlined italics, deletions struck-through:
Mylotarg is intended for
administration under the supervision of a physician who is experienced in the use of cancer
chemotherapeutic agents. Mylotarg should be
administered under the supervision of
physicians experienced in the treatment of acute leukemia and in facilities
equipped to monitor and treat leukemia patients.
The following sentence was removed from the INDICATION AND USAGE section and placed in the WARNINGS section as the second paragraph:
There are no controlled trials demonstrating efficacy and safety using Mylotarg in combination with other chemotherapeutic agents.
Hepatotoxicity subsection revised with additions in bolded, underlined italics, deletions struck-through:
Hepatotoxicity, including severe
VOD,
has been reported in association with the use of Mylotarg. Patients who receive
Mylotarg either before or after hematopoietic
stem-cell transplant
HSCT, and
patients with underlying hepatic disease or abnormal
liver function may be at increased
risk for developing severe VOD. Death from liver failure and from VOD has been
reported in patients who received Mylotarg.
Use in Patients with Hepatic Impairment:
Second sentence revised:
Extra caution should be exercised when administering Mylotarg in patients with hepatic impairment (see ADVERSE REACTIONS section).
PRECAUTIONS:
Revised with additions in bolded, underlined italics, deletions struck-through:
General, Treatment by Experienced Physicians subsection:
Treatment should be initiated by and
remain under the supervision of a physician who
is experienced in the use of cancer
chemotherapeutic agents. Mylotarg should be
administered under the supervision of
physicians experienced in the treatment of
acute leukemia and in facilities
equipped to monitor and treat leukemia patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No long-term studies in animals have
been performed to evaluate the carcinogenic potential of Mylotarg. Gemtuzumab
ozogamicin was clastogenic in the mouse in vivo micronucleus test. This positive
result is consistent with the known ability of calicheamicin to cause
double-stranded breaks in DNA. Formal fertility studies were
not conducted in animals. When given
weekly for 6 doses to rats, gemtuzumab ozogamicin caused atrophy of the
seminiferous tubules, oligospermia, desquamated cells in the epididymis, and
hyperplasia of the interstitial cells at the dose of 1.2 mg/kg/week (approximately 0.9 times
the human dose on a mg/m 2 basis).
These
findings did not resolve following a
5-week recovery period. Gemtuzumab
ozogamicin adversely affected male, but not female, fertility in rats. Following daily administration of gemtuzumab ozogamicin to male rats for 28 days at doses of 0.02 to 0.16 mg/kg/day (approximately 0.01 to 0.11 times the human dose on a mg/m 2 basis) gemtuzumab ozogamicin caused: decreased fertility rates, epididymal sperm counts, and sperm motility; increased incidence of sperm abnormalities; and microscopic evidence of decreased spermatogonia and spermatocyte count. These findings did not resolve following a 9-week recovery period.
OTHER CLINICAL EXPERIENCE is changed to Other Clinical Experience because this is a subsection of ADVERSE REACTIONS
Revised with additions in bolded, underlined italics, deletions struck-through:
In post-marketing experience and
other clinical trials, additional cases of VOD have been reported, some with in association
with the use of other chemotherapeutic agents,
underlying hepatic disease/abnormal
liver function, or a history of prior or subsequent
HSCT transplant. Renal failure
secondary to TLS, hypersensitivity reactions, anaphylaxis, and pulmonary events,
have also been reported in association with the use of
Mylotarg. (See WARNINGS section).
DOSAGE AND ADMINISTRATION:
Last sentence deleted:
The recommended dose of Mylotarg is 9
mg/m 2 ,
administered as a 2-hour intravenous infusion. Physicians should consider
leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood
count to below 30,000/µL
prior to administration of Mylotarg. Appropriate measures (e.g.
hydration and allopurinol) must be taken to prevent hyperuricemia. Patients should
receive the following prophylactic medications one hour before Mylotarg administration:
diphenhydramine 50 mg po and acetaminophen 650- 1000 mg po; thereafter, two
additional doses of acetaminophen 650-1000 mg po, one every 4 hours as needed. Vital signs
should be monitored during infusion and for four hours following infusion. The
recommended treatment course with Mylotarg is a total of 2 doses with 14 days between the
doses. Full recovery from hematologic toxicities is not a requirement for administration of
the second dose. Mylotarg may be administered in an
outpatient setting.
[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#orlaam ]
[At beginning of Physician Package Insert]
BOX WARNING:
Revised text in bolded, underlined italics -
ORLAAM, used for the treatment of opiate addiction, shall be dispensed only by opioid treatment programs (OTPs) certified by SAMHSA under 42 CFR Part 8, and registered by the Drug Enforcement Administration under 21. U.S.C. 823(g)(1). This does not preclude the maintenance or detoxification treatment of a patient who is hospitalized for medical conditions other than opiate addiction and who requires temporary maintenance for concurrent opiate addiction during the critical period of the patient’s hospitalization. Failure to abide by these requirements may result in injunction precluding operation of the program, seizure of the drug supply, revocation of the program approval, and possible criminal prosecution.
ORLAAM has no recommended uses outside of the treatment of opiate addiction.
INDIVIDUALIZATION OF DOSAGE:
Tenth paragraph, revisions in bolded, underlined italics -
Most patients do not experience withdrawal during the 72-hour inter-dose interval after reaching pharmacological steady-state with or without adjustment of the Friday dose. If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM, small doses of supplemental methadone should be given rather than giving ORLAAM on two consecutive days. Take-home doses of ORLAAM and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion (see DOSAGE AND ADMINISTRATION).
WARNINGS:
[First box warning in WARNINGS section]
Second sentence, second paragraph deleted -
"Routine daily dosing after a patient has been inducted onto ORLAAM treatment is not allowed by current treatment regulations."
Risk of Overdose:
Deleted text struck-through -
Due to
these risks of diversion and accidental death, ORLAAM has been
approved for use only when dispensed by a licensed facility and
is not given in take-home doses.
PRECAUTIONS:
Interaction with Narcotic Antagonists, Mixed Agonists/Antagonists, Partial Agonists, and Pure Agonists
New text in bolded, underlined italics -
As with other mu agonists, patients maintained on ORLAAM may experience withdrawal symptoms when administered pure narcotic antagonists, such as naloxone, naltrexone, and nalmefene, or when administered mixed agonists/antagonists or partial agonists such as pentazocine, nalbuphine, butorphanol, and buprenorphine [previously "...administered pure narcotic antagonists, mixed agonists/antagonists or partial agonists such as naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine."]
Use in Pregnancy
First paragraph, last sentence, deleted -
"Current regulations mandate monthly pregnancy tests in female patients of childbearing potential who are using ORLAAM."
Pediatric Use
Second sentence, deletion is struck-through -
Its use is not recommended and is contrary
to current regulations.
INDUCTION:
Third paragraph revised, new text in bolded, underlined italics -
Most patients can tolerate the 72-hour inter-dose interval during the induction period. Some patients may require additional intervention (see INDIVIDUALIZATION OF DOSAGE). If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM, supplemental methadone in small doses should be given rather than giving ORLAAM on two consecutive days. Take-home doses of ORLAAM and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion.
The heading "PLANNED TEMPORARY INTERRUPTION OF ORLAAM MAINTENANCE:"
was deleted and replaced with
"TAKE-HOME DOSES"
The entire section (3 paragraphs) was deleted and replaced with the following:
If it is determined that a patient is responsible in handling opioid drugs than ORLAAM take-home doses are permitted. Refer to 42 CFR Part 8 for specific restrictions.
SAFETY AND HANDLING:
Second paragraph, the following revisions were made with new text in bolded, underlined italics, deleted text struck-through:
For the first six to twelve months, sales of ORLAAM will be
restricted to clinics that
have received training in its use, until there is general knowledge about how to
use the drug safely.
Sales of ORLAAM are restricted to clinics that have received training
in its
use. Since ORLAAM can be potentially dangerous if diverted,
appropriate security measures should be taken
to safeguard stock of ORLAAM as required by 21 CFR 1301.74.
CLINICAL STUDIES:
Long-Term Maintenance Treatment of Erosive Esophagitis:
Additional information regarding comparative studies results of Prevacid vs. ranitidine in the long-term maintenance treatment of erosive esophagitis.
New third paragraph:
In a U.S. randomized, double-blind, study, PREVACID 15 mg q.d. (n=100) was compared with ranitidine 150 mg b.i.d (n=106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12-month period. Treatment with PREVACID resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p<0.001). In addition, PREVACID was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with PREVACID remained asymptomatic for a significantly longer period of time than those treated with ranitidine.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Antisecretory Activity
Revisions in bolded, underlined italics
Table entitled:
"Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH"
-----------------Median pH on day 7----------------
Third paragraph deleted:
"A double-blind crossover study compared pantoprazole 40 mg with omeprazole 20 mg once daily for 7 days. For both one day and one
week treatment periods, pantoprazole administered in the morning produced significantly greater increases in median pH during 24 hours
than did omeprazole."
PRECAUTIONS:
Second paragraph deleted -
"No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The pharmacokinetics of pantoprazole has not been well characterized in patients with severe hepatic impairment. Therefore, the potential for modest drug accumulation (</=21%) when dosed once daily needs to be weighed against the potential for reduced acid control when dosed every other day in these patients."
DOSAGE AND ADMINISTRATION
Treatment of Erosive Esophagitis
Second paragraph, first sentence revised with revisions in bolded, underlined italics:
No dosage adjustment is necessary in patients with ["mild, moderate or severe" deleted] renal ["insufficeincy" deleted] impairment, hepatic impairment or for elderly patients. No dosage adjustment is necessary in patients undergoing hemodialysis.
Labeling provides for the use of RESCRIPTOR for the treatment of
HIV-1 infection in combination with at least 2 other active antiretroviral agents when therapy is
warranted. Labeling extensively revised, Contact the company for a copy of the new labeling/package insert.
Return to Quick Reference
Item 2 revised with revisions in bolded, underlined italics:
Patients currently dependent on opioids, including those currently maintained on opiate agonists [e.g., methadone or LAAM (levo-alpha-acetyl-methadol)].
PRECAUTIONS:
Information for Patients
Third sentence of paragraph three revised with revisions in bolded, underlined italics:
Most important, however, if you attempt to self-administer large doses of heroin or any other opioid (including methadone or LAAM) while on ReVia, you may die or sustain serious injury, including coma.
ADVERSE REACTIONS:
Observed During Clinical Practice:
Respiratory:
Added to subsection:
"Oropharyngeal irritation"
[ For more information regarding these changes go to the following link: http://www.fda.gov/medwatch/safety/2001/safety01.htm#sporan ]
Capsule labeling changes summarized below:
1. Information concerning congestive heart failure in patients receiving Sporanox has been added to the
Boxed Warning, CLINICAL PHARMACOLOGY/Special Populations/Decreased Cardiac Contractility, CONTRAINDICATIONS/Congestive Heart Failure, WARNINGS/Cardiac Dysrythmias, WARNINGS/Cardiac Disease, PRECAUTIONS/Information for Patients and ADVERSE REACTIONS/Post-marketing Experience.
2. Dofetilide has been added to the list of Drug Interactions in the Black Box,
CONTRAINDICATIONS/Drug Interactions, and PRECAUTIONS/ Drug Interactions/Antiarrythmics. Astemizole has been deleted from these sections of the label and the PRECAUTIONS/Drug Interactions/Antihistamine statement regarding astemizole has also been deleted.
3. Information describing Sporanox as a CYP3A4 inhibitor causing increased plasma concentration
levels of certain co-administered drugs has been added to the Boxed Warnings, CONTRAINDICATIONS/Drug Interactions and PRECAUTIONS/ Drug Interactions. This information has also been added to the following drug classes in PRECAUTIONS/ Drug
Interactions: Anticonvulsants, Antimycobacterials, Antipsychotics, Macrolide Antibiotics, Non-nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors and alfentanil and trimetrexate listed in the "Other" category.
4. A statement has been added to INDICATIONS AND USAGE advising that prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
5. Information concerning hepatotoxicity in patients receiving Sporanox has been added to CLINICAL
PHARMACOLOGY/Special Populations/Hepatic Insufficiency, CONTRAINDICATIONS/Hepatitis, WARNINGS/Hepatic Effects, ADVERSE REACTIONS and ADVERSE REACTIONS/Post-marketing Experience.
6. The CLINICAL PHARMACOLOGY/Special Populations/Renal Insufficiency subsection was revised to provide a more complete description of the results of the pharmacokinetic study in renally impaired patients.
7. Information concerning the negative inotropic effect of dihydropyridine calcium channel blockers in patients receiving Sporanox has been added to PRECAUTIONS/Calcium Channel Blockers.
8. The following drugs have been added to PRECAUTIONS/Drug Interactions:
· alfentanil · alprazolam · atorvastatin · busulfan · buspirone · cerivastatin · clarithromycin · docetaxel · dofetilide · erythromycin · nevirapine
· omeprazole · pimozide · saquinavir · sirolimus · trimetrexate · verapamil
Additionally, this section has been reorganized to include new class names.
9. Menstrual disorders was added to rare cases described in ADVERSE REACTIONS/Post-marketing
Experience.
Injection labeling changes summarized below:
A Macrolide Antibiotics statement has been added to PRECAUTIONS/Drug Interactions, and clarithromycin and erythromycin are included in that statement. A Protease Inhibitor statement including saquinavir, indinavir and ritonavir has also been added to PRECAUTIONS/Drug Interactions.
1. Information concerning congestive heart failure in patients receiving Sporanox has been added to the Boxed Warning, CLINICAL PHARMACOLOGY/Special Populations/Decreased Cardiac Contractility, CONTRAINDICATIONS/Congestive Heart Failure, WARNINGS/Cardiac Dysrythmias, WARNINGS/Cardiac Disease, and ADVERSE REACTIONS/Post-marketing Experience.
2. Dofetilide has been added to the list of Drug Interactions in the Boxed Warning, CONTRAINDICATIONS/Drug Interactions, and PRECAUTIONS/ Drug Interactions/Antiarrythmics. Astemizole has been deleted from these sections of the label and the PRECAUTIONS/Drug Interactions/Antihistamine statement regarding astemizole has also been deleted.
3. Information describing Sporanox as a CYP3A4 inhibitor causing increased plasma concentration levels of certain co-administered drugs has been added to the Boxed Warning, CONTRAINDICATIONS/Drug Interactions and PRECAUTIONS/ Drug Interactions.
This information has also been added to the following drug classes in PRECAUTIONS/ Drug Interactions: Anticonvulsants, Antimycobacterials, Antipsychotics, Macrolide Antibiotics, Non-nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors and alfentanil and
trimetrexate listed in the "Other" category.
4. Information concerning hepatotoxicity in patients receiving Sporanox has been added to CLINICAL PHARMACOLOGY/Special Populations/Hepatic Insufficiency, CONTRAINDICATIONS/Hepatitis, WARNINGS/Hepatic Effects, ADVERSE
REACTIONS and ADVERSE REACTIONS/Post-marketing Experience.
5. Information concerning the negative inotropic effect of dihydropyridine calcium channel blockers in patients receiving Sporanox has been added to PRECAUTIONS/Calcium Channel Blockers.
6. The following drugs have been added to PRECAUTIONS/Drug Interactions:
· alfentanil · alprazolam · atorvastatin · buspirone · cerivastatin · clarithromycin · docetaxel · dofetilide · erythromycin · nevirapine
· pimozide · saquinavir · sirolimus · trimetrexate · verapamil
Additionally, this section has been reorganized to include new class names.
7. Menstrual disorders was added to rare cases described in ADVERSE REACTIONS/Post-marketing
Experience.
Oral Solution labeling summarized below:
1. Information concerning congestive heart failure in patients receiving Sporanox has been added to the Boxed Warning, CLINICAL PHARMACOLOGY/Special Populations/Decreased Cardiac Contractility, CONTRAINDICATIONS/Congestive
Heart Failure, WARNINGS/Cardiac Dysrythmias, WARNINGS/Cardiac Disease, PRECAUTIONS/Information for Patients and ADVERSE REACTIONS/Post-marketing Experience.
2. Dofetilide has been added to the list of Drug Interactions in the Boxed Warning, CONTRAINDICATIONS/Drug Interactions, and PRECAUTIONS/ Drug Interactions/Antiarrythmics. Astemizole has been deleted from these sections of the label and the PRECAUTIONS/Drug Interactions/Antihistamine statement regarding astemizole has also been deleted.
3. Information describing Sporanox as a CYP3A4 inhibitor causing increased plasma concentration levels of certain co-administered drugs has been added to the Boxed Warning, CONTRAINDICATIONS/Drug Interactions and PRECAUTIONS/ Drug Interactions. This information has also been added to the following drug classes in PRECAUTIONS/ Drug Interactions: Anticonvulsants, Antimycobacterials, Antipsychotics, Macrolide Antibiotics, Non-nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors and alfentanil and trimetrexate listed in the "Other" category.
4. Information concerning hepatotoxicity in patients receiving Sporanox has been added to CLINICAL PHARMACOLOGY/Special Populations/Hepatic Insufficiency, CONTRAINDICATIONS/Hepatitis, WARNINGS/Hepatic Effects, ADVERSE REACTIONS and ADVERSE REACTIONS/Post-marketing Experience.
5. The CLINICAL PHARMACOLOGY/Special Populations/Renal Insufficiency subsection was revised to provide a description of a pharmacokinetic study of itraconazole capsules in renally impaired patients.
6. Information concerning the negative inotropic effect of dihydropyridine calcium channel blockers in patients receiving Sporanox has been added to PRECAUTIONS/Calcium Channel Blockers.
7. The following drugs have been added to PRECAUTIONS/Drug Interactions:
· alfentanil · alprazolar · atorvastatin · bisulfan · buspirone · cerivastatin · clarithromycin · docetaxel · dofetilide · erythromycin · nevirapine · omeprazole · pimozide · saquinavir · sirolimus · trimetrexate · verapamil
Additionally, this section has been reorganized to include new class names.
8. Menstrual disorders was added to rare cases described in ADVERSE
REACTIONS/Post-marketing Experience.
The new labeling provides for revisions of the package insert, cartons, and containers to reflect the use of a new trademark, Tobraflex. Please note that the previous trademark, Tobrasone, will no longer be used in labeling.
WARNINGS:
9th paragraph, 1st sentence revised with new text in bolded, underlined italics -
Coadministration of oral midazolam in patients who are taking ketoconazole, itraconazole and saquinavir has been shown to result in large increases in C max and AUC of midazolam due to a decrease in plasma clearance of midazolam (see PHARMACOKINETICS: Drug-Drug Interactions and PRECAUTIONS).
PRECAUTIONS:
New text in bolded, underlined italics -
Information for Patients: To assure safe and effective use of VERSED Syrup, the following information and instructions should be communicated to the patient when appropriate:
1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication antibiotics and protease inhibitors, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.
Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, saquinavir, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.
DOSAGE AND ADMINISTRATION:
4th paragraph, end of 2nd sentence
New text in bolded, underlined italics -
Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants and concomitant medications which may potentially cause a more intense and prolonged sedation (see PRECAUTIONS: Drug Interactions)
9th paragraph, 2nd sentence
In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications and medical need.
[Labeling for Injection, Injection Premixed ]
CLINICAL PHARMACOLOGY:
Pharmacokinetics
The following subsection was added:
Geriatrics:
The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3.1 hours. (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function).
PRECAUTIONS
The following revisions have been made to the Geriatric Use subsection:
The previous label read:
Use in Elderly Patients:
Ulcer healing rates in elderly patients (65 to 82 years of age), were no different from those in younger age-groups. The incidence rates for adverse events and laboratory abnormalities were also not different from those seen in other age-groups."
The revised label reads:
Geriatric Use:
Clinical studies of ZANTAC Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. However, in clinical studies of oral formulations of ZANTAC, of the total number of subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup analyses, 4197 were 65 and over, while 899 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function.
DOSAGE AND ADMINISTRATION:
Dosage Adjustment for Patients With Impaired Renal Function subsection:
The following was added:
Elderly patients are more likely to have decreased renal function, therefore care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Use and PRECAUTIONS: Geriatric Use).
[Labeling for Tablets, Syrup, GELdose Capsules, EFFERdose Tablets and Granules ]
CLINICAL PHARMACOLOGY
Pharmacokinetics -
The following subsection was added:
Geriatrics -
The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak levels average 526 following a 150 mg twice daily dose and occur in about 3 hours (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function).
PRECAUTIONS:
The following revisions have been made to the Geriatric Use subsection
The previous label read:
Use in Elderly Patients:
Ulcer healing rates in elderly patients (65 to 82 years of age), were no different from those in younger age-groups. The incidence rates for adverse events and laboratory abnormalities were also not different from those seen in other age-groups."
The revised label reads:
Geriatric Use:
Of the total number of subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup analyses, 4197 were 65 and over, while 899 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal Function."
DOSAGE AND ADMINISTRATION:
Dosage Adjustment for Patients With Impaired Renal Function:
The following was added:
Elderly patients are more likely to have decreased renal function, therefore care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Use and PRECAUTIONS: Geriatric Use).
Some of the labeling modified in order to be in agreement with revisions made to the other Zovirax products.
DESCRIPTION:
First paragraph, first sentence revised -
"an antiviral drug" was removed and replaced with, "a synthetic nucleoside analogue active against herpes viruses".
VIROLOGY:
Section added:
Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative or quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.
CLINICAL PHARMACOLOGY:
The revised CLINICAL PHARMACOLOGY section reads:
Two clinical pharmacology studies were performed with ZOVIRAX Ointment 5% in immunocompromised adults at risk of developing mucocutaneous Herpes simplex virus infections or with localized varicella-zoster infections. These studies were designed to evaluate the dermal tolerance, systemic toxicity, and percutaneous absorption of acyclovir.
In 1 of these studies, which included 16 inpatients, the complete ointment or its vehicle were randomly administered in a dose of 1-cm strips (25 mg acyclovir) 4 times a day for 7 days to an intact skin surface area of 4.5 square inches. No local intolerance, systemic toxicity, or contact dermatitis were observed. In addition, no drug was detected in blood and urine by radioimmunoassay (sensitivity, 0.01 mcg/mL).
The other study included 11 patients with localized varicella-zoster infections. In this uncontrolled study, acyclovir was detected in the blood of 9 patients and in the urine of all patients tested. Acyclovir levels in plasma ranged from <0.01 to 0.28 mcg/mL in 8 patients with normal renal function, and from <0.01 to 0.78 mcg/mL in 1 patient with impaired renal function. Acyclovir excreted in the urine ranged from <0.02% to 9.4% of the daily dose. Therefore, systemic absorption of acyclovir after topical application is minimal.
CLINICAL TRIALS section added. Previously, this information was located in the INDICATIONS AND USAGE section of the label.
The CLINICAL TRIALS section now reads:
CLINICAL TRIALS: In clinical trials of initial genital herpes infections, ZOVIRAX Ointment 5% has shown a decrease in healing time and, in some cases, a decrease in duration of viral shedding and duration of pain. In studies in immunocompromised patients mainly with herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain.
In studies of recurrent genital herpes and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit; there was some decrease in duration of viral shedding.
INDICATIONS AND USAGE section revised.
The following paragraphs deleted:
INDICATIONS AND USAGE: ZOVIRAX (acyclovir) Ointment 5% is indicated in the management of initial herpes genitalis and in limited nonlife-threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients. In clinical trials of initial herpes genitalis, ZOVIRAX Ointment 5% has shown a decrease in healing time and, in some cases, a decrease in duration of viral shedding and duration of pain. In studies in immunocompromised patients with mainly herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain.
By contrast, in studies of recurrent herpes genitalis and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit; there was some decrease in duration of viral shedding.
Replaced with the following:
INDICATIONS AND USAGE: ZOVIRAX (acyclovir) Ointment 5% is indicated in the management of initial genital herpes and in limited non-life-threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients.
PRECAUTIONS:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Previous labeling:
Carcinogenesis, Mutagenesis, Impairment of Fertility: Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of 50, 150, and 450 mg/kg per day given by gavage. These studies showed no statistically significant difference in the incidence of benign and malignant tumors produced in drug-treated as compared to control animals, nor did acyclovir induce the occurrence of tumors earlier in drug-treated animals as compared to controls. In two in vitro cell transformation assays, used to provide preliminary assessment of potential oncogenicity in advance of these more definitive lifetime bioassays in rodents, conflicting results were obtained. Acyclovir was positive at the highest dose used in one system and the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. Acyclovir was negative in another transformation system.
No chromosome damage was observed at maximum tolerated parenteral doses of 100 mg/kg acyclovir in rats or Chinese hamsters; higher doses of 500 and 1000 mg/kg were clastogenic in Chinese hamsters. In addition, no activity was found in a dominant lethal study in mice. In nine of 11 microbial and mammalian cell assays, no evidence of mutagenicity was observed. In two mammalian cell assays (human lymphocytes and L5178Y mouse lymphoma cells in vitro), positive response for mutagenicity and chromosomal damage occurred, but only at concentrations at least 1000 times the plasma levels achieved in humans following topical application.
Acyclovir does not impair fertility or reproduction in mice at oral doses up to 450 mg/kg/day or in rats at subcutaneous doses up to 25 mg/kg/day. In rabbits given a high dose of acyclovir (50 mg/kg/day s.c.), there was a statistically significant decrease in implantation efficiency.
Revised to read:
Carcinogenesis, Mutagenesis, Impairment of Fertility: Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis, and fertility are not included in the full prescribing information for ZOVIRAX Ointment 5% due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for ZOVIRAX Capsules, Tablets, and Suspension and ZOVIRAX for Injection.
Pregnancy: Teratogenic Effects:
Pregnancy Category was changed from C to B.
Previous labeling:
Pregnancy Category C. Acyclovir was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and i.v.), or in standard tests in the rat (50 mg/kg/day, s.c.). In a nonstandard test in rats, fetal abnormalities, such as head and tail anomalies, were observed following subcutaneous administration of acyclovir at very high doses associated with toxicity to the maternal rat. The clinical relevance of these findings is uncertain.8 There are no adequate and well-controlled studies in pregnant women. Acyclovir should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Revised to read:
Pregnancy Category B. Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure. There are no adequate and well-controlled studies of systemic acyclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy 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 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 less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Systemic acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers:
Previous labeling:
It is not known whether topically applied acyclovir is excreted in breast milk. After oral administration of ZOVIRAX, acyclovir concentrations have been documented in breast milk in two women and ranged from 0.6 to 4.1 times the corresponding plasma levels.9, 10 These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Caution should be exercised when ZOVIRAX Ointment is administered to a nursing woman.
Revised to read:
It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of ZOVIRAX, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.
Geriatric:
Subsection was added:
Clinical studies of ZOVIRAX Ointment 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. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS:
Previous labeling:
Because ulcerated genital lesions are characteristically tender and sensitive to any contact or manipulation, patients may experience discomfort upon application of ointment. In the controlled clinical trials, mild pain (including transient burning and stinging) was reported by 103 (28.3%) of 364 patients treated with acyclovir and by 115 (31.1%) of 370 patients treated with placebo; treatment was discontinued in 2 of these patients. Other local reactions among acyclovir-treated patients included pruritus in 15 (4.1%), rash in 1 (0.3%), and vulvitis in 1 (0.3%). Among the placebo-treated patients, pruritus was reported by 17 (4.6%) and rash by 1 (0.3%).
In all studies, there was no significant difference between the drug and placebo group in the rate or type of reported adverse reactions nor were there any differences in abnormal clinical laboratory findings.
Revised to read:
In the controlled clinical trials, mild pain (including transient burning and stinging) was reported by about 30% of patients in both the active and placebo arms; treatment was discontinued in 2 of these patients. Local pruritus occurred in 4% of these patients. In all studies, there was no significant difference between the drug and placebo group in the rate or type of reported adverse reactions nor were there any differences in abnormal clinical laboratory findings. Observed During Clinical Practice: Based on clinical practice experience in patients treated with ZOVIRAX Ointment in the US, spontaneously reported adverse events are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as part of the underlying disease process. Voluntary reports of adverse events that have been received since market introduction include: General: Edema and/or pain at the application site. Skin: Pruritus, rash.
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