SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES
APPROVED BY FDA
October 1996
(modified 1/29/97 & 5/19/97: for Valtrex
modified 7/21/97: for Calcijex)
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 1996 Physicians' Desk Reference (PDR), if drug's labeling
included in the PDR.
(Click on name of the product to go
directly to the summary.)
AZULFIDINE EN-TABS (sulfasalazine) -
CALCIJEX (calcitrol) -
DIDRONEL (etidronate disodium) -
ERYTHROCIN (erythromycin lactobionate for injection, USP) -
LOZOL (indapamide) -
MEFOXIN (cefoxitin) -
MEGACE(megestrol acetate) -
MIACALCIN(calcitonin-salmon) -
NIMOTOP (nimodipine) -
NOVANTRONE (mitoxantrone) -
PAXIL (paroxetine HCl) -
RETROVIR (zidovudine) -
ROCALTROL (calcitriol) -
SULAR (nisoldipine) -
VALTREX (valacyclovir HCl) -
ZOLOFT (sertraline HCl)
AZULFIDINE EN-TABS
(sulasalazine)
[October 17, 1996: Pharmacia]
-
CLINICAL PHARMACOLOGY:
- Revised, with several specific new subsections including
Pharmacodynamics, Pharmacokinetics (In vivo, Absorption,
Distribution, Metabolism and Excretion), Special Populations
(Elderly, Acetylator Status and Gender) [see complete section in package
insert].
- PRECAUTIONS:
- Information for Patients subsection revised, with
notation that occurrence of sore throat, fever, pallor, purpura or
jaundice may indicate a serious blood disorder, and that patients should
seek medical advice should any of these occur. Patients are now advised
to swallow the tablets whole.
Rheumatoid Arthritis (new sub-subsection): Rheumatoid
arthritis rarely remits, therefore continued administration of
Azulfidine is indicated; patients requiring sulfasalazine should
follow up with their physicians to determine need for continued
administration.
Laboratory Tests: Revised, with notation that CBCs, including
differential WBC and LFTs, should be performed prior to starting
Azulfidine and every second week during the first three months of
therapy. During the second three months, the same tests should be
done once monthly and thereafter every three months, and as clinically
indicated. Periodic urinalysis renal function assessment should also
be done during Azulfidine treatment. Determination of serum
sulfapyridine levels may be useful since concentrations > 50 ug/ml
appear to be associated with an increased incidence of adverse
reactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Revised to include results of two year oral carcinogenicity studies
in male and female rats and mice, and results of mutagenicity studies;
previously noted reproductive studies performed in rats and rabbits
regarding impairment of male fertility to have added mg/kg and mg/m2
dosing information [see complete section in package insert].
Pediatric Use: Revised to note that the safety and
effectiveness of Azulfidine in 1) children below two years of
age with ulcerative colitis, and 2) juvenile rheumatoid arthritis,
has not been established, and that it has been reported that the
frequency of adverse events in patients with systemic onset of
juvenile arthritis is high.
- DOSAGE AND ADMINISTRATION:
- Revised, including separating into individual
subsections for Ulcerative Colitis and Rheumatoid Arthritis
[see complete section in package insert].
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CALCIJEX
(calcitriol)
[October 22, 1996: Abbott]
-
PRECAUTIONS:
- Essential Laboratory Tests: Statement added -
"Adynamic bone
disease may develop if PTH levels are suppressed to abnormal levels.
If biopsy is not being done for other (diagnostic)
reasons, PTH levels may be used to indicate the rate of bone
turnover. If PTH levels fall below 20 pmol/L or 200 mg/ml in patients
treated with Calcijex, the Calcijex dose should be
reduced or therapy discontinued."
- DOSAGE AND ADMINISTRATION:
-
Paragraph on the recommended initial dose of Calcijex deleted and replaced with -
"The recommended initial dose of Calcijex, depending on the severity of the
hypocalcemia and/or secondary hyperparathyroidism, is 1.0 mcg (0.02 mcg/kg)
to 2.0 mcg administered three times weekly, approximately every other day. Doses as small as
0.5 mcg and as large as 4.0 mcg three times weekly have been used as an initial dose.
If a satisfactory response is not observed, the dose may be increased by 0.5 to 1.0 mcg at two to four week
intervals. During this titration period, serum calcium and phosphorus levels should be
obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate
product greater than 70 is noted, the drug should be immediately discontinued until
these parameters are appropriate. Then, the Calcijex dose should be reinitiated at a lower dose.
Doses may need to be reduced as the PTH levels decrease in response to the therapy.
Thus, incremental dosing must be individualized and commensurate with PTH, serum
calcium and phosphorus levels.
The following is a suggested approach in dose titration:
PTH Levels |
Calcijex Dose |
the same or increasing |
increase |
decreasing by > 30%, < 60% |
maintain |
decreasing by > 60% |
decrease |
one and on-half to three times normal range |
maintain |
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DIDRONEL
(etidronate disodium)
[October 4, 1996: Proctor & Gamble]
-
ADVERSE REACTIONS:
- Worldwide Postmarketing Experience: Addition of statement
that there have been rare reports
of exacerbation of asthma.
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ERYTHROCIN
(erythromycin lactobionate
for injection, USP)
[October 11, 1996: Abbott]
-
CLINICAL PHARMACOLOGY:
- 1. "After absorption" added to beginning of previous sentence
"Erythromycin diffuses readily into most body fluids";
- 2. In phrase "passage of the drug across the blood-brain barrier
increases in meningitis", "in meningitis" changed to "when the
meninges are inflamed";
- 3. Previous statement regarding crossing of placental
barrier/breast milk excretion changed to "Erythromycin crosses
the placental barrier, but fetal plasma levels are low. The drug is
excreted in human milk".
CONTRAINDICATIONS:
-
Revised by addition of statement that erythromycin is
contraindicated in patients taking terfenadine or astemizole
(see PRECAUTIONS, Drug Interactions).
WARNINGS:
- Revised by addition of the following information:
- 1.
There have been reports suggesting that erythromycin does not
reach the fetus in adequate concentration to prevent congenital
syphilis. Infants born to women treated during pregnancy with
oral erythromycin for early syphilis should be treated with an
appropriate penicillin regimen;
- 2. Rhabdomyolysis with or without renal impairment has been
reported in seriously ill patients receiving erythromycin
concomitantly with lovastatin. Therefore,
patients receiving concomitant lovastatin and erythromycin
should be carefully monitored for creatine kinase (CK) and
serum transaminase levels (see package insert for lovastatin);
- 3. Benzyl alcohol has been reported to be associated with a
fatal "Gasping Syndrome" in premature infants;
- 4. Pseudomembranous colitis has been reported with nearly
all antibacterial agents, including erythromycin, and may range
in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with
diarrhea subsequent to the
administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora
of the colon and may permit overgrowth of clostridia. Studies
indicate that a toxin produced by Clostridium difficule
is a primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established,
therapeutic measures should be initiated. Mild cases of
pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases, consideration
should be given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial drug clinically
effective against C. difficule colitis.
-
PRECAUTIONS:
- Drug Interactions: Revised by addition of the following
information (*revisions made for consistency with labeling of other
erythromycin preparations):
- 1.
Statement that increased anticoagulation effects due to this drug
may be more pronounced in the elderly added to previous statement
regarding reports of increased anticoagulant effects
with concomitant erythromycin/oral anticoagulants;
- *2. Statement that concurrent use of erythromycin and ergotamine
or dihydroergotamine has been associated in some patients with
acute ergot toxicity characterized by severe peripheral vasospasm
and dysesthesia;
- *3. Statement that erythromycin has been reported to decrease
the clearance of triazolam and midazolam and, thus, may increase
the pharmacologic effect of these benzodiazepines.
-
Drug/Laboratory Test Interactions (new subsection): Erythromycin
interferes with the fluorometric determination of urinary
catecholamines.
- ADVERSE REACTIONS:
- Revised by addition of the following information:
- 1.
Previous statement regarding cardiac arrhythmias revised to note
that rarely erythromycin has been associated with the production
of ventricular arrhythmias, including ventricular tachycardia and
torsades de pointes, in individuals with prolonged QTc intervals;
- 2. Statement that skin reactions ranging from mild eruptions
to erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis have been reported rarely added to
previous statement regarding allergic reactions;
- 3. Statement that onset of pseudomembranous colitis symptoms
may occur during or after antibacterial treatment (see WARNINGS)
added.
- OVERDOSAGE:
-
*Revised to note that in the case of overdosage, erythromycin
should be discontinued. Overdosage should be handled with the
prompt elimination of unabsorbed drug and all other appropriate
measures should be instituted. Erythromycin is not removed by
peritoneal dialysis or hemodialysis.
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LOZOL
(indapamide)
[October 29, 1996: Rhone-Poulenc Rorer]
-
WARNINGS:
-
Paragraph regarding hyponatremia revised to indicate that severe
cases of hyponatremia, accompanied by hypokalemia, have been reported
with recommended doses of indapamide. This occurred primarily in elderly
females and appears to be dose-related. In addition, a large
case-controlled pharmacoepidemiology study indicates there is an
increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses.
As before, it is noted that hyponatremia considered possibly
clinically significant (less than 125 mEq/L) has not been
observed in clinical trials with the 1.25 mg dosage (see PRECAUTIONS).
Thus, patients should be started at the 1.25 mg dose and maintained
at the lowest possible dose (see DOSAGE AND ADMINISTRATION).
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MEFOXIN
(cefoxitin)
[October 11, 1996: Merck]
-
ADVERSE REACTIONS:
-
Renal Function: Subsection revised to indicate that in addition
to the adverse events listed in relation to Mefoxin, the following
adverse reactions/altered laboratory test results have been
reported for cephalosporin class antibiotics: urticaria, erythema
multiforme, Stevens-Johnson
syndrome, serum sickness-like reactions, abdominal pain, colitis,
renal dysfunction, toxic nephropathy, false-positive test for
urinary glucose, hepatic dysfunction including cholestasis,
elevated bilirubin, aplastic anemia, hemorrhage, prolonged
prothrombin time, pancytopenia,
agranulocytosis, superinfection, and vaginitis including
vaginal candidiasis. Several cephalosporins have been implicated
in triggering seizures, particularly in patients with renal impairment
when the dosage was not reduced (see DOSAGE). If seizures
associated with drug therapy occur, the drug should be
discontinued; anticonvulsant therapy can be given if clinically
indicated.
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MEGACE
(megestrol acetate) Oral Suspension
[October 22, 1996: Bristol-Myers Squibb]
-
CONTRAINDICATIONS:
-
History of hypersensitivity to megestrol acetate or any
component of the formulation added as a contraindication.
WARNINGS:
-
Revised to include new paragraph stating that although
the glucocorticoid activity of Megace Oral Suspension has
not been fully evaluated, laboratory evidence of adrenal
suppression has been observed. Clinical cases of new
onset diabetes, exacerbation of pre-existing diabetes, and
Cushing's syndrome have been reported in association with
the use of Megace. Rare cases of clinically apparent adrenal
insufficiency have also been reported in association with
the use of Megace. The possibility of adrenal suppression
should be considered in any patient taking or withdrawing from
chronic Megace therapy who presents with symptoms of adrenal
insufficiency such as hypotension, nausea, vomiting, dizziness,
or weakness. Laboratory evaluation for adrenal insufficiency
and replacement stress doses of a rapidly acting glucocorticoid
may be indicated for such patients.
PRECAUTIONS:
-
General: Previous statement regarding glucocorticoid
effects/adrenal suppression deleted (see new WARNINGS paragraph
outlined above).
Use in Diabetics (new subsection): Exacerbation of pre-existing
diabetes with increased insulin requirements have been reported in
association with the use of Megace.
Drug Interactions: Revised to note that pharmacokinetic
studies show that there are no alterations in
pharmacokinetic parameters when megestrol acetate is administered
with zidovudine or with rifabutin.
ADVERSE REACTIONS:
-
Postmarketing (new subsection): Postmarketing reports
associated with Megace Oral Suspension
include thromboembolic phenomena including thrombophlebitis and
pulmonary embolism, and glucose intolerance (see WARNINGS and
PRECAUTIONS sections).
STORAGE:
-
Previous instruction to store Megace Oral Suspension at or
below 25 degrees C revised, with new instruction to store between
15-25 degrees C (59-77 degrees F).
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MIACALCIN
(calcitonin-salmon)
[October 22, 1996: Sandoz]
-
PRECAUTIONS:
-
Information for Patients: Revised to include the following,
of which patients should be
advised:
-
Store new, unassembled bottles in the refrigerator between 360-460F (20-80C);
- Protect the product from freezing;
- Before priming the pump and using a new bottle, allow it to
reach room temperature;
- After a new bottle is assembled, it should be stored at room
temperature in an upright position. Each bottle contains 14
doses;
- Discard all unrefrigerated bottles after 30 days;
- See DOSAGE AND ADMINISTRATION, Priming (Activation) of Pump
for complete instructions on priming the pump and
administering Miacalcin (calcitonin-salmon)
Nasal Spray.
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NIMOTOP
(nimodipine)
[October 24, 1996: Bayer]
-
PRECAUTIONS:
-
General: Advisement added that intravenous administration of
the contents of Nimotop
Capsules has resulted in serious adverse consequences including
hypotension, cardiovascular
collapse, and cardiac arrest.
DOSAGE AND ADMINISTRATION:
-
Advisement added that the contents of NimotopR Capsules must not
be administered by
intravenous injection or other parenteral routes.
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NOVANTRONE
(mitoxantrone)
[October 18, 1996: Immunex]
-
PRECAUTIONS and ADVERSE REACTIONS:
-
Statement added that Topoisomerase II inhibitors, including
Novantrone, in combination with
other antineoplastic agents, have been associated with the
development of acute leukemia.
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PAXIL
(paroxetine HCl)
[October 17, 1996: SmithKline Beecham]
-
OVERDOSAGE:
-
Human Experience: Revised to note that overdose with Paxil
(up to 2000 mg) alone and in
combination with other drugs has been reported. Signs and
symptoms of overdose with Paxil
include nausea, vomiting, sedation, dizziness, sweating, and
facial flush; there are no reports
of coma or convulsions following overdosage with Paxil alone.
A fatal outcome has been
reported rarely when Paxil was taken in combination with other
agents, or when taken alone.
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RETROVIR
(zidovudine)
[October 4, 1996: Glaxo-Wellcome]
-
CLINICAL PHARMACOLOGY:
-
Pharmacokinetics: Nursing Mothers (new subsection): Previous
advisement against
breastfeeding by HIV-infected women (see PRECAUTIONS, Nursing
Mothers) included, as is
new information that after administration of a single dose
of 200 mg zidovudine to 13 HIV-infected women, mean concentration
of zidovudine was similar in human milk and serum.
PRECAUTIONS:
-
Nursing Mothers: Paragraph concerning whether zidovudine
is excreted in human milk or reduced potential for HIV transmission
in breast milk removed; replaced by statement that
zidovudine is excreted in human milk (see Pharmacokinetics).
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ROCALTROL
(calcitriol)
[October 22, 1996: Hoffman-La Roche]
-
ADVERSE REACTIONS:
-
Statement added that one case of erythema multiforme and one case
of allergic reaction
(swelling of lips and hives all over the body) were confirmed by
rechallenge.
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SULAR
(nisoldipine)
[October 23, 1996: Zeneca]
-
PRECAUTIONS:
-
Pediatric Use (new subsection): Safety and effectiveness in
pediatric patients have not been
established.
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VALTREX
(valacyclovir HCl) Caplets
[October 4, 1996: Glaxo Wellcome]
-
CLINICAL PHARMACOLOGY:
-
Clinical Trials: Section revised to provide information supporting new indication
"Treatment of initial episode of genital herpes".
-
INDICATIONS AND USAGE:
-
Section revised to incorporate new indication.
- WARNINGS:
-
Last two sentences - "Valtrex is not indicated for the treatment of
immunocompromised patients.
This syndrome has not been observed in immunocompetent patients treated with Valtrex in
clinical trials." deleted.
The section now reads (all bold) "Thombotic thrombocytopenic purpura/hemolytic
uremic syndrome
(TTP/HUS), in some cases resulting in death, has occurred (replacing
"been reported") in
patients with advanced HIV disease and also in allogeneic bone marrow transplant and
renal transplant recipients participating in clinical trials of
Valtrex at doses of 8 grams per
day." (Italicized words are new.)
- PRECAUTIONS:
-
First sentence revised to read "The efficacy of Valtrex has not
been established for the treatment
of disseminated herpes zoster, or suppression of recurrent genital herpes, or in
immunocompromised patients."
Information for Patients: Genital Herpes (formerly called "Recurrent Genital Herpes"):
Last sentence of subsection - "There are no data on the effectiveness of
treatment with Valtrex when initiated
more than 24 hours after the onset of signs or symptoms." deleted and replaced by
New second paragraph - "There are no data on the effectiveness of treatment
initiated more than 72 hours
after the onset of signs and symptoms of a first episode of genital
herpes or more than
24 hours of the onset of signs and symptoms of a recurrent episode."
- ADVERSE REACTIONS
- Table 1. "Incidence (%) of Adverse Events in Herpes Zoster and
Genital Herpes Study
Populations" revised - see labeling/package insert.
- DOSAGE AND ADMINISTRATION:
- Section revised to incorporate information about new indication, including
revision of Table 2: Dosages for Patients with Renal Impairment.
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ZOLOFT
(sertraline HCl)
[October 25, 1996: Pfizer]
-
PRECAUTIONS:
-
General:
Activation of Mania/Hypomania: Revised to indicate that activation of
mania/hypomania has also been reported in a small proportion of patients with
Major Affective Disorder treated with other marketed antidepressant and antiobsessional
drugs [italicized words added].
Seizure: Revised to indicate that while no seizures were observed among approximately
3000 patients treated with Zoloft in the depression development program, 4 patients out of
approximately 1800 exposed during the obsessive compulsive disorder (OCD) development
program experienced seizures, representing a crude incidence of 0.2%. Three of these patients
were adolescents, two with a seizure disorder and one with a family history of seizure disorder,
none of whom were receiving anticonvulsant medication. Thus, like other antidepressant and
antiobsessional drugs, Zoloft should be introduced with care in patients with a seizure
disorder.
Information for Patients: Advisement against concomitant use of Zoloft and
alcohol in depressed patients expanded to OCD patients.
Drug Interactions:
Drugs Metabolized by P450 3A4 (new subsection): Sertraline was
co-administered with cytochrome P450 3A4 substrates (terfenadine or
carbamazepine), under steady-state conditions, in two separate in vivo interaction studies. The
results of these studies demonstrated that sertraline co-administration did not increase plasma
concentrations of terfenadine or carbamazepine, suggesting that sertraline's extent of inhibition of
P450 3A4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants (TCAs) (new subsection): The extent to which
SSRI-TCA interactions may pose clinical problems will depend on the degree of
inhibition and pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the
co-administration of TCAs with Zoloft, because sertraline may inhibit TCA metabolism. Plasma
TCA concentrations may need to be monitored, and TCA dose may need to be reduced, during
co-administration with Zoloft (see Drugs Metabolized by P450 2D6 under
PRECAUTIONS).
Alcohol: Recommendation against concomitant use of Zoloft and alcohol
in
depressed patients expanded to OCD patients.
Carcinogenesis: Revised by deleting maximum recommended human dose
(MRHD) comparisons based on mg/kg; all the previously delineated carcinogenesis studies
now have MRHD values expressed on a mg/m2 basis.
Impairment of Fertility: Revised by deleting MRHD comparison based on
mg/kg.
- PREGNANCY - PREGNANCY CATEGORY C:
-
Pregnancy Category has been changed from B to C.
Teratogenic Effects and Non-teratogenic Effects subsection designations
have been eliminated, with the following new paragraph under PREGNANCY -
PREGNANCY CATEGORY C:
"Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day
and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the
maximum recommended human dose (MRHD) on a mg/m2 basis. There was no
evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline
during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10
mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the
MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during
the last third of gestation and throughout lactation, there was an increase in the number of
stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body
weights were also decreased during the first four days after birth. These effects occurred at a
dose of 20 mg/kg (1 times the MHRD on a mg/m2 basis). The no effect dose for rat
pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m2 basis). The decrease
in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of
these effects is unknown. There are no adequate and well-controlled studies in pregnant women.
Zoloft should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus."
- ADVERSE REACTIONS:
-
Commonly Observed: Among patients treated with Zoloft in placebo controlled
premarketing studies added to beginning of subsection outlining the most commonly
observed adverse events associated with Zoloft use and not seen at an equivalent incidence among
placebo treated patients.
New paragraph added: "In placebo-controlled clinical trials for OCD, adverse events
observed at an incidence of at least 5% for Zoloft and at an incidence that was twice or more
the incidence among placebo-treated patients included: nausea, insomnia, diarrhea, decreased
libido, anorexia, dyspepsia, ejaculation failure (primarily ejaculatory delay), tremor, and increased
sweating."
Associated with Discontinuation of Treatment: Patients substituted for
"subjects"
in first sentence.
New paragraph added: "In placebo-controlled clinical trials for OCD, 10% of patients treated
with Zoloft discontinued treatment due to an adverse event. The more common events were
nausea, insomnia, and diarrhea."
Incidence in Controlled Clinical Trials:
Depression: Table outlining treatment-emergent adverse experience
incidence in placebo-controlled clinical trials for depression (now called Table 1) has
been revised, with percentages rounded to the nearest whole number. As before, events reported
by at least 1% of patients treated with Zoloft are included in Table 1, with the new exception of
those events which had an incidence on placebo greater than or equal to Zoloft. The latter are
listed below, but are not included in, Table 1.
Obsessive Compulsive Disorder (new subsection): Contains a table (Table
2) which enumerates adverse events that occurred at a frequency of 2% or more
among patients on Zoloft who participated in controlled trials comparing Zoloft with placebo in
the treatment of OCD [see complete subsection in package insert].
Other Events Observed During the Premarketing Evaluation of Zoloft (sertraline
hydrochloride) New notation added: "The safety profile observed in OCD patients
treated with Zoloft is similar to the safety profile in depressed patients."
- DOSE AND ADMINISTRATION:
- Initial Treatment: With respect to effect/effectiveness, or/and
antiobsessive added to antidepressant where appropriate. A new statement recommends a
dose of 50 mg, administered once daily, as the initial dose.
Maintenance/Continuation/Extended Treatment:
New paragraph added:
"Although the efficacy of Zoloft beyond 12 weeks of dosing for OCD has not been
documented in controlled trials, OCD is a chronic condition, and it is reasonable to
consider continuation for a responding patient. Dosage adjustments may be needed to maintain
the patient on the lowest effective dosage, and patients should be periodically reassessed to
determine the need for continued treatment."
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