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Zoloft

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Zoloft

SIDE EFFECTS

During its premarketing assessment, multiple doses of ZOLOFT were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.

Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Incidence in Placebo-Controlled Trials

Table 2 enumerates the most common treatment-emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for ZOLOFT and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with ZOLOFT and with incidence greater than placebo who participated in controlled clinical trials comparing ZOLOFT with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.

TABLE 2 : MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS

Body System/Adverse Event Percentage of Patients Reporting Event
Major Depressive Disorder/Other* OCD Panic Disorder PTSD
ZOLOFT
(N=861)
Placebo
(N=853)
ZOLOFT
(N=533)
Placebo
(N=373)
ZOLOFT
(N=430)
Placebo
(N=275)
ZOLOFT
(N=374)
Placebo
(N=376)
Autonomic Nervous System Disorders
  Ejaculation Failure1 7 < 1 17 2 19 1 11 1
  Mouth Dry 16 9 14 9 15 10 11 6
  Sweating Increased 8 3 6 1 5 1 4 2
Center. & Periph. Nerv. System Disorders
  Somnolence 13 6 15 8 15 9 13 9
  Tremor 11 3 8 1 5 1 5 1
  Dizziness 12 7 17 9 10 10 8 5
General
  Fatigue 11 8 14 10 11 6 10 5
  Pain 1 2 3 1 3 3 4 6
  Malaise < 1 1 1 1 7 14 10 10
Gastrointestinal Disorders
  Abdominal Pain 2 2 5 5 6 7 6 5
  Anorexia 3 2 11 2 7 2 8 2
  Constipation 8 6 6 4 7 3 3 3
  Diarrhea/Loose Stools 18 9 24 10 20 9 24 15
  Dyspepsia 6 3 10 4 10 8 6 6
  Nausea 26 12 30 11 29 18 21 11
Psychiatric Disorders
  Agitation 6 4 6 3 6 2 5 5
  Insomnia 16 9 28 12 25 18 20 11
  Libido Decreased 1 < 1 11 2 7 1 7 2
  PMDD Daily Dosing PMDD Luteal Phase Dosing2 Social Anxiety Disorder  
Body System/Adverse Event ZOLOFT
(N=121)
Placebo
(N=122)
ZOLOFT
(N=136)
Placebo
(N=127)
ZOLOFT
(N=344)
Placebo
(N=268)
   
Autonomic Nervous System Disorders    
  Ejaculation Failure1 N/A N/A N/A N/A 14 -    
  Mouth Dry 6 3 10 3 12 4    
  Sweating Increased 6 < 1 3 0 11 2    
Center. & Periph. Nerv. System Disorders    
  Somnolence 7 < 1 2 0 9 6    
  Tremor 2 0 < 1 < 1 9 3    
  Dizziness 6 3 7 5 14 6    
General    
  Fatigue 16 7 10 < 1 12 6    
  Pain 6 < 1 3 2 1 3    
  Malaise 9 5 7 5 8 3    
Gastrointestinal Disorders    
  Abdominal Pain 7 < 1 3 3 5 5    
  Anorexia 3 2 5 0 6 3    
  Constipation 2 3 1 2 5 3    
  Diarrhea/Loose Stools 13 3 13 7 21 8    
  Dyspepsia 7 2 7 3 13 5    
  Nausea 23 9 13 3 22 8    
Psychiatric Disorders    
  Agitation 2 < 1 1 0 4 2    
  Insomnia 17 11 12 10 25 10    
  Libido Decreased 11 2 4 2 9 3    
1Primarily ejaculatory delay. Denominator used was for male patients only (N=271 ZOLOFT major depressive disorder/other*; N=271 placebo major depressive disorder/other*; N=296 ZOLOFT OCD; N=219 placebo OCD; N=216 ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo PTSD; No male patients in PMDD studies; N=205 ZOLOFT social anxiety disorder; N=153 placebo social anxiety disorder). *Major depressive disorder and other premarketing controlled trials.
2The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2 should be avoided.

TABLE 3 : TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of Patients Reporting Event Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety Disorder combined

Body System/Adverse Event** ZOLOFT
(N=2799)
Placebo
(N=2394)
Autonomic Nervous System Disorders
  Ejaculation Failure1 14 1
  Mouth Dry 14 8
  Sweating Increased 7 2
Center. & Periph. Nerv. System Disorders
  Somnolence 13 7
  Dizziness 12 7
  Headache 25 23
  Paresthesia 2 1
  Tremor 8 2
Disorders of Skin and Appendages
  Rash 3 2
Gastrointestinal Disorders
  Anorexia 6 2
  Constipation 6 4
  Diarrhea/Loose Stools 20 10
  Dyspepsia 8 4
  Nausea 25 11
  Vomiting 4 2
General
  Fatigue 12 7
Psychiatric Disorders
  Agitation 5 3
  Anxiety 4 3
  Insomnia 21 11
  Libido Decreased 6 2
  Nervousness 5 4
Special Senses
  Vision Abnormal 3 2
1Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
**Included are events reported by at least 2% of patients taking ZOLOFT except the following events, which had an incidence on placebo greater than or equal to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain, pharyngitis, respiratory disorder, upper respiratory tract infection.

Associated With Discontinuation In Placebo-Controlled Clinical Trials

Table 4 lists the adverse events associated with discontinuation of ZOLOFT (sertraline hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for ZOLOFT in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.

TABLE 4 : MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS

Adverse Event Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety Disorder combined
(N=2799)
Major Depressive Disorder/ Other*
(N=861)
OCD
(N=533)
Panic Disorder
(N=430)
PTSD
(N=374)
PMDD Daily Dosing
(N=121)
PMDD Luteal Phase Dosing
(N=136)
Social Anxiety Disorder
(N=344)
Abdominal Pain - - - - - - - 1%
Agitation - 1% - 2% - - - -
Anxiety - - - - - - - 2%
Diarrhea/ Loose Stools 2% 2% 2% 1% - 2% - -
Dizziness - - 1% - - - - -
Dry Mouth - 1% - - - - - -
Dyspepsia - - - 1% - - - -
Ejaculation Failure1 1% 1% 1% 2% - N/A N/A 2%
Fatigue - - - - - - - 2%
Headache 1% 2% - - 1% - - 2%
Hot Flushes - - - - - - 1% -
Insomnia 2% 1% 3% 2% - - 1% 3%
Nausea 3% 4% 3% 3% 2% 2% 1% 2%
Nervousness - - - - - 2% - -
Palpitation - - - - - - 1% -
Somnolence 1% 1% 2% 2% - - - -
Tremor - 2% - - - - - -
1Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205 social anxiety disorder).
*Major depressive disorder and other premarketing controlled trials.

Male And Female Sexual Dysfunction With SSRIs

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.

Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients taking ZOLOFT in placebo-controlled trials.

Table 5

Adverse Event ZOLOFT Placebo
Ejaculation failure* (primarily delayed ejaculation) 14% 1%
Decreased libido** 6% 1%
*Denominator used was for male patients only (N=1118 ZOLOFT; N=926 placebo)
**Denominator used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)

There are no adequate and well-controlled studies examining sexual dysfunction with sertraline treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Other Adverse Events in Pediatric Patients

In over 600 pediatric patients treated with ZOLOFT, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with ZOLOFT): fever, hyperkinesia, urinary incontinence, aggressive reaction, sinusitis, epistaxis and purpura.

Other Events Observed During the Premarketing Evaluation of ZOLOFT (sertraline hydrochloride)

Following is a list of treatment-emergent adverse events reported during premarketing assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except those already listed in the previous tables or elsewhere in labeling.

In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced an event of the type cited on at least one occasion while receiving ZOLOFT. All events are included except those already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to be uninformative and those for which a causal relationship to ZOLOFT treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; Rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.

Autonomic Nervous System Disorders–Frequent: impotence; Infrequent: flushing, increased saliva, cold clammy skin, mydriasis; Rare: pallor, angle-closure glaucoma, priapism, vasodilation.

Body as a Whole–General Disorders–Rare: allergic reaction, allergy.

Cardiovascular–Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.

Central and Peripheral Nervous System Disorders–Frequent: hypertonia, hypoesthesia; Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.

Disorders of Skin and Appendages–Infrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.

Endocrine Disorders–Rare: exophthalmos, gynecomastia.

Gastrointestinal Disorders–Frequent: appetite increased; Infrequent: dysphagia, tooth caries aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.

General–Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors, generalized edema; Rare: face edema, aphthous stomatitis.

Hearing and Vestibular Disorders–Rare: hyperacusis, labyrinthine disorder.

Hematopoietic and Lymphatic–Rare: anemia, anterior chamber eye hemorrhage.

Liver and Biliary System Disorders–Rare: abnormal hepatic function.

Metabolic and Nutritional Disorders–Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction.

Musculoskeletal System Disorders–Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis, muscle cramps, muscle weakness.

Psychiatric Disorders–Frequent: yawning, other male sexual dysfunction, other female sexual dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion.

Reproductive–Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute female mastitis.

Respiratory System Disorders–Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.

Special Senses–Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field defect.

Urinary System Disorders–Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.

Laboratory Tests–In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with ZOLOFT (sertraline hydrochloride) administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.

The safety profile observed with ZOLOFT treatment in patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.

Other Events Observed During the Post marketing Evaluation of ZOLOFT

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

Drug Abuse And Dependence

Controlled Substance Class

ZOLOFT (sertraline hydrochloride) is not a controlled substance.

Physical and Psychological Dependence

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans, ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. In animal studies ZOLOFT does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of ZOLOFT misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Read the Zoloft (sertraline hcl) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins

Because sertraline is tightly bound to plasma protein, the administration of ZOLOFT (sertraline hydrochloride) to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound ZOLOFT by other tightly bound drugs.

In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either ZOLOFT (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared to a 1% decrease for placebo (p < 0.02). The normalization of prothrombin time for the ZOLOFT group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when ZOLOFT therapy is initiated or stopped.

Cimetidine

In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.

Drugs that Prolong the QT Interval

The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval (e.g., some antipsychotics and antibiotics) (see PRECAUTIONS).

CNS Active Drugs

In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p < 0.03). There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the placebo group (p < 0.03). The clinical significance of these changes is unknown.

In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-state lithium levels or the renal clearance of lithium.

Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the lithium dose.

In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS).

Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.

The effect of ZOLOFT on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of ZOLOFT therapy with appropriate adjustments to the valproate dose.

The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of ZOLOFT and such drugs is required.

There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.

Drugs Metabolized by P450 3A4

In three separate in vivo interaction studies, sertraline was coadministered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).

Drugs Metabolized by P450 2D6

Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT may require lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS).

Serotonergic Drugs

See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.

Triptans

There have been Rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including ZOLOFT, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGSSerotonin Syndrome).

Sumatriptan

There have been Rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)

The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the 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 the dose of TCA may need to be reduced, if a TCA is co-administered with ZOLOFT (see Drugs Metabolized by P450 2D6 under PRECAUTIONS).

Hypoglycemic Drugs

In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.

Atenolol

ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.

Digoxin

In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.

Microsomal Enzyme Induction

Preclinical studies have shown ZOLOFT to induce hepatic microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when ZOLOFT is initiated or discontinued.

Electroconvulsive Therapy

There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and ZOLOFT.

Alcohol

Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol is not recommended.

Read the Zoloft Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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