Summary Of Exposure |
A) USES: Sertraline is used for depressive disorders, panic attacks, anxiety, obsessive-compulsive disorders and posttraumatic stress disorders.
B) EPIDEMIOLOGY: Sertraline overdose is fairly common, but only rarely results in serious toxicity. However, deaths have occasionally been reported.
C) PHARMACOLOGY: It is a selective serotonin reuptake inhibitor (SSRI).
D) TOXICOLOGY: Typically, sertraline overdose is mainly associated with CNS depression. Seizures have rarely been reported. Serotonergic toxicity, especially after congestions with other serotonergic agents (MAO inhibitors, serotonin releasers, and other serotonin reuptake inhibitors) may be observed. QTc prolongation, but not torsade de pointes has been reported.
E) WITH THERAPEUTIC USE
1) COMMON: Agitation, insomnia, headache, dizziness, somnolence, and fatigue are among the most frequently reported adverse effects of sertraline. Other effects include:
2) NEUROLOGIC/PSYCHIATRIC: Ataxia, incoordination, vertigo, abnormal dreams, aggressive behavior, delusions, hallucinations, emotional lability, paranoia, suicidal ideation, akathisia, tingling, extrapyramidal symptoms, dystonia, exacerbation of tics, mania, and depersonalization, and feelings of panic.
3) CARDIOVASCULAR: Palpitations, chest pain, hypertension, hypotension, edema, peripheral ischemia, syncope, and tachycardia.
4) GASTROINTESTINAL: Nausea, diarrhea, dysphagia, gastritis, glossitis, gum hyperplasia, hiccups, stomatitis, tenesmus, constipation, indigestion, anorexia, flatulence, abdominal pain, increased appetite, eructation, and tongue ulceration.
5) GENITOURINARY: Incontinence, urinary frequency, dysuria, urinary retention, urinary incontinence, dysmenorrhea, intermenstrual bleeding, amenorrhea, menorrhagia, leukorrhea, atrophic vaginitis, gynecomastia, galactorrhea, breast pain, and breast enlargement. and renal pain.
6) OCULAR: Exophthalmos, xerophthalmia, blurred vision, diplopia, photophobia, tearing, conjunctivitis, eye pain, and mydriasis.
7) MUSCULOSKELETAL: Myalgia, arthralgia, and dystonia.
8) RESPIRATORY: Bronchospasm, dyspnea, cough, and hyperventilation.
9) OTHER: Diaphoresis, dermatitis, hyponatremia secondary to SIADH, and elevated liver enzymes.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Somnolence, dizziness, agitation, nausea, vomiting, constipation, diarrhea, tachycardia, palpitations, hypertension, mydriasis, elevated liver enzymes, and cutaneous vasodilation.
2) SEVERE TOXICITY: Marked CNS depression. Serotonergic toxicity, such as hyperreflexia, clonus, altered mental status, or hemodynamic instability may be seen, usually when sertraline is taken in combination with other serotonergic agents, but serotonin syndrome has been reported after sertraline overdose. Seizures have been reported. Hyponatremia secondary to SIADH has been reported following overdose and has been severe enough to cause seizures.
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Vital Signs |
3.3.2) RESPIRATIONS
A) WITH POISONING/EXPOSURE 1) Increased respirations have been reported after an overdose (Adson et al, 2001).
3.3.3) TEMPERATURE
A) WITH POISONING/EXPOSURE 1) CASE REPORT: Hyperthermia has been reported in a pediatric toxic ingestion of sertraline. Two hours postingestion, a 9-year-old boy presented with an oral temperature of 38.5 degrees C. He was transferred to an intensive care unit due to persistent symptoms, which included a rectal temperature of 42.2 degrees C (Kaminski et al, 1994).
3.3.4) BLOOD PRESSURE
A) WITH POISONING/EXPOSURE 1) Hypotension has occurred following an acute overdose of sertraline (Kaminski et al, 1994).
3.3.5) PULSE
A) WITH POISONING/EXPOSURE 1) Increased pulse rate may occur following an overdose in both adults and children (Adson et al, 2001; Kaminski et al, 1994). Increased pulse rate was seen in a pediatric overdose. A heart rate of greater than 200 bpm was observed (Kaminski et al, 1994).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Sertraline has caused exophthalmos, xerophthalmia, blurred vision, diplopia, photophobia, tearing, conjunctivitis, eye pain, and mydriasis (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
B) WITH POISONING/EXPOSURE 1) Mydriasis associated with serotonin syndrome has been reported following a sertraline overdose (Brendel et al, 2000).
2) NYSTAGMUS: CASE REPORT: An 18-year-old woman with a history of epilepsy presented with agitation, disorientation and noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 6 hours later (Eren Cevik et al, 2014).
3.4.6) THROAT
A) WITH POISONING/EXPOSURE 1) Severe angioedema, with tongue swelling and compromised airway, was reported following a combined sertraline 6000 mg and trazodone 1300 mg overdose (Adson et al, 2001).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) Sertraline has been associated with palpitations (frequent), chest pain (frequent), hypertension, hypotension, edema, peripheral ischemia, syncope, and tachycardia (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
B) ELECTROCARDIOGRAM ABNORMAL 1) WITH THERAPEUTIC USE a) Electrocardiographic abnormalities were reported in 2 of 8 patients taking sertraline 200 mg daily for 7 weeks (Amin et al, 1989). 1) One patient developed T-wave flattening, and one developed clinically significant Q-T interval prolongation.
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 40-year-old woman presented to the emergency department (ED) with fatigue and drowsiness after ingesting sertraline 2250 mg , temazepam 400 mg , and diazepam 200 mg . Her initial ECG on admission, approximately 3 hours postingestion, showed normal sinus rhythm with a QT interval of 370 ms (QTc 420 ms) and negative T waves in leads V1-V3. Twenty-four hours later, a repeat ECG showed a prolonged QT interval of 520 ms (QTc 525 ms) with deepened negative T waves in leads V1-V3. The ECG abnormalities normalized with supportive care, and the patient was transferred for psychiatric evaluation (de Boer et al, 2005).
C) TACHYARRHYTHMIA 1) WITH POISONING/EXPOSURE a) Mild sinus tachycardia was reported in 4 of 6 adult cases of overdose (Kassner & Woolf, 1992). Hypertension and prolonged tachycardia with a heart rate of greater than 200 beats per minute (bpm) was seen in a pediatric sertraline overdose (Kaminski et al, 1994).
b) CASE REPORT: Following an intentional overdose of sertraline 4000 mg and naproxen 7700 mg, a 14-year-old girl experienced delayed onset seizures 4.5 hours postingestion, followed by sustained sinus tachycardia (102 to 108 bpm). The patient recovered and was discharged to psychiatric care 2 days later (Meier & Lam, 1998).
c) CASE REPORT: Severe sinus tachycardia (pulse greater than 170 bpm) was reported after overdose in 2 adolescent girls (Mordel & Linden, 1998).
D) VENTRICULAR TACHYCARDIA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 63-year-old man, with a history of depression, infective endocarditis status-post prosthetic mitral valve replacement and hypertension, presented to the ED with complaints of shocks fro m his implantable cardioverter-defibrillator. Upon admission, his pulse rate was 185 bpm and his ECG showed sustained monomorphic ventricular tachycardia (VT). Inspection of the device showed multiple episodes of VT in the ventricular fibrillation zone, resulting in discharges when antitachycardia packing failed to convert the VT. Possible triggering factors such as electrolyte abnormalities, drugs of abuse or sleep apnea were ruled out. However, the only significant change in history was an increase in sertraline from 100 mg/day to 150 mg/day in the prior 3 days. The patient reported a similar increase in dose 2 years prior during his first episode of VT. His dose was decreased to 100 mg/day and his ECG returned to normal sinus rhythm. Once the patient was stable, the Naranjo nomogram scale was applied with a score of 9, indicating a "definite" association of sertraline with VT in this patient (Patel et al, 2013).
E) LACK OF EFFECT 1) WITH THERAPEUTIC USE a) In a case-control study of patients (smokers) hospitalized with a first myocardial infarction (MI) (n=653), non-SSRI antidepressant users (n=510) were reported to have a nonsignificant reduction in MI risk, whereas users of SSRIs (n=143) (including sertraline) were reported to have a reduced odds of MI. An odds ratio of 0.35 was reported for MI among current SSRI users compared with nonusers. It was suggested that SSRIs may confer a protective effect against MI due to their inhibitory effect on serotonin-mediated platelet activation (Sauer et al, 2001).
3.5.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) LACK OF EFFECT a) When tested in the dog, doses of 0.1 mg/kg, 0.4 mg/kg, and 1 mg/kg intravenously caused little or no cardiovascular effect (Koe et al, 1983a).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) BRONCHOSPASM 1) WITH THERAPEUTIC USE a) Rhinitis, pharyngitis, bronchospasm, dyspnea, cough, and hyperventilation have occasionally been associated with sertraline (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
2) WITH POISONING/EXPOSURE a) OVERDOSE: Death due to asthma exacerbation was reported in an 18-year-old woman following a sertraline overdose (blood concentration 620 ng/mL). The authors suggest that in a variant of the serotonin syndrome, a large dose of a selective serotonin reuptake inhibitor can help precipitate an asthma attack or prevent the patient from being aware of the evolution of an exacerbation (Carson et al, 2000).
B) HYPERVENTILATION 1) WITH POISONING/EXPOSURE a) Increased respiratory rate has been associated with a sertraline overdose in a pediatric patient (Kaminski et al, 1994).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) PSYCHOMOTOR AGITATION 1) WITH POISONING/EXPOSURE a) Acute overdoses may commonly result in agitation (Adson et al, 2001).
b) CASE REPORTS: Extreme agitation leading to insomnia was seen in a 15-month-old who ingested up to 200 mg (Pers Comm., 1992). Extreme agitation exhibited by hand biting, extremely uncooperative, and hostility was seen in a 9-year-old patient following an acute overdose (Kaminski et al, 1994).
c) CASE REPORT: An 18-year-old woman with a history of epilepsy presented with agitation, disorientation and noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 6 hours later (Eren Cevik et al, 2014).
B) SEIZURE 1) WITH POISONING/EXPOSURE a) Severe sertraline toxicity may rarely result in seizures. In one case, a delayed onset of seizures was reported. 1) CASE REPORT: A delayed grand mal seizure, occurring 4.5 hours following an overdose of sertraline 4000 mg and naproxen 7700 mg was reported in a 14-year-old girl. A second seizure occurred 5.5 hours postingestion. Serum sertraline serum level of greater than 1000 ng/mL (normal 16 to 78 ng/mL) and no anion gap was reported on serum chemistry. The girl was discharged to psychiatric care 2 days later (Meier & Lam, 1998).
C) MYOCLONIC SEIZURE 1) WITH THERAPEUTIC USE a) CASE REPORT: A 23-year-old woman had a history of an intentional ingestion of an organophosphorus compound and had 2 generalized seizures during recovery; a CT scan was normal. She was then started on sertraline (25 mg/day) for ongoing depression and the dose was gradually titrated to 150 mg/day over a 4 week period. Her clinical symptoms improved and she remained stable for 8 months. Around this time, she reported myoclonic jerks of her shoulder and hands that occurred a few times a day and then increased to 10 times a day over a week. She then developed one episode of generalized tonic-clonic seizure. An EEG study showed no epileptiform activity and laboratory studies were within normal limits. Sertraline was gradually reduced to 25 mg/day and it was noted that myoclonic jerks were decreased to 1 to 2 times per day. Sertraline was discontinued with no further clinical symptoms and no reports of depression (Sarkar et al, 2014).
D) DROWSY 1) WITH POISONING/EXPOSURE a) Lethargy was reported in 6 of 6 adult overdoses (Kassner & Woolf, 1992). Somnolence was reported following an overdose of up to 8 g sertraline alone in a 51-year-old woman (Brendel et al, 2000).
E) FINE MOTOR IMPAIRMENT 1) WITH THERAPEUTIC USE a) Mattila et al (1988) evaluated the acute effects of single doses of sertraline 100 mg, amitriptyline 50 mg, and placebo on psychomotor performance in 12 subjects older than 50 years in a double-blind, placebo-controlled crossover study (Mattila et al, 1988). 1) While performance was clearly impaired by amitriptyline, sertraline caused no significant impairment. In addition, sertraline slightly improved objective measures of alertness.
2) Although subjective drowsiness was reported with both drugs, the effect was less with sertraline.
b) Hindmarch & Bhatti (1988) observed increases in objective measurements of alertness with sertraline in doses of 50 mg, 75 mg, and 100 mg in a double-blind, placebo-controlled study (Hindmarch & Bhatti, 1988). 1) Cognitive function tests (critical flicker fusion and choice reaction time tests) were performed on 10 patients after single doses. Measurement parameters were significantly improved compared with placebo from 3 to 7.5 hours after ingestion.
2) However, subjective drowsiness was reported with these doses.
c) Saletu et al (1986) reported that higher doses of sertraline (200 to 400 mg) may impair psychometric performance (Saletu et al, 1986). d) Extrapyramidal effects, including jaw stiffness, torticollis responsive to treatment with diphenhydramine, and akathisia have been reported (Shihabuddin & Rapport, 1994). e) Exacerbation of tics in a patient with Tourette syndrome that responded to cessation of sertraline use have been reported (Hauser & Zesiewicz, 1995). F) MANIC BEHAVIOR 1) WITH THERAPEUTIC USE a) CASE REPORTS: Laporta et al (1987) reported 2 cases of hypomania, one occurring after 5 weeks of sertraline 200 mg/day, and one after 100 mg/day for 9 weeks (Laporta et al, 1987). 1) In both cases, symptoms resolved upon discontinuation of sertraline and treatment with short-term clonazepam or lithium.
G) CENTRAL NERVOUS SYSTEM FINDING 1) WITH THERAPEUTIC USE a) Agitation, insomnia, headache, dizziness, somnolence, and fatigue are among the most frequently reported adverse effects of sertraline.
b) Other effects include ataxia, incoordination, vertigo, abnormal dreams, aggressive behavior, delusions, hallucinations, emotional lability, paranoia, suicidal ideation, akathisia tingling, feelings of panic, and depersonalization (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008; Reimherr et al, 1990).
c) Saletu et al (1986) reported anxiety, giddiness, and restlessness with single 200 mg and 400 mg doses of sertraline (Saletu et al, 1986).
d) Tandan et al (1997) reported 3 patients with neurally mediated syncope, which was exacerbated following the use of sertraline (Tandan et al, 1997).
e) Complex, colorful visual hallucinations have been reported less than 3 weeks after initiation of sertraline therapy in a 38-year-old man. Hallucinations were present daily for 30 to 40 seconds after awakening and resolved following discontinuation of sertraline (Bourgeois et al, 1998).
2) WITH POISONING/EXPOSURE a) A pediatric patient presented with hallucinations as well as extreme psychomotor agitation following an acute overdose. His pupils were fixed and dilated and slowly reactive to light. Deep tendon reflexes were 3+ (Kaminski et al, 1994).
b) CASE REPORT: An 18-year-old woman with a history of epilepsy presented with agitation, disorientation and noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 6 hours later (Eren Cevik et al, 2014).
H) TREMOR 1) WITH THERAPEUTIC USE a) Sertraline has been associated with hypertonia, myalgia, paresthesias, and muscle twitching on rare occasions (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
b) Tremor has been reported with single doses of 200 mg and 400 mg (Saletu et al, 1986).
2) WITH POISONING/EXPOSURE a) Tonic shaking activity in all extremities became intense over several hours in a pediatric patient following an acute overdose. On the third hospital day, a mild tremor was still present (Kaminski et al, 1994).
I) DYSTONIA 1) WITH THERAPEUTIC USE a) Extrapyramidal effects, including jaw stiffness, torticollis responsive to treatment with diphenhydramine, and akathisia have been reported (Shihabuddin & Rapport, 1994).
b) Extrapyramidal effects, including dystonic reactions, may occur following therapeutic doses. Painful upper lip dystonia was reported in an adult following daily sertraline (50 mg daily) for 6 months. The dystonic reaction resolved on discontinuation of sertraline, but resumed on drug rechallenge (Stanislav & Childs, 1999).
c) Reversible parkinsonism has been reported in a 90-year-old man following several months of sertraline therapy (with dose increased to 150 mg/day 2 weeks prior to onset of extrapyramidal effects). Sertraline was tapered down over 2 weeks to 50 mg/day, with complete reversal of parkinsonism (Schechter & Nunes, 1997).
J) SEROTONIN SYNDROME 1) WITH THERAPEUTIC USE a) CASE REPORT: Serotonin syndrome (hyperactivity, hyperreflexia, tremor, sinus tachycardia, hypertension) was reported in a 16-year-old girl following a single sertraline 100 mg dose. Symptoms resolved following cyproheptadine dosing (Horowitz & Mullins, 1999).
b) CASE REPORT: Serotonin syndrome (hypomania, myoclonus, diaphoresis, hot-cold feeling) was reported following therapeutic doses of citalopram. After a washout period, sertraline was prescribed, with the same symptoms returning in 3 days. Symptoms resolved within 3 days of discontinuing the medication (Voirol et al, 2000).
2) WITH POISONING/EXPOSURE a) Sertraline, a selective serotonin reuptake inhibitor, is capable, as are other drugs in this class, of inducing a serotonin syndrome. Most often, this syndrome is induced by concurrent use of 2 or more drugs capable of enhancing CNS serotonin activity. Often, patients with serotonin syndrome will respond to discontinuation of sertraline and supportive care alone (Adson et al, 2001; Horowitz & Mullins, 1999; Lane & Baldwin, 1997). Serotonin syndrome has been reported following an overdose of sertraline with no coingestants (Brendel et al, 2000). b) CASE REPORT: Clinical signs suggestive of serotonin syndrome were exhibited in a pediatric overdose case. The patient presented with agitation, delirium, tachycardia, skin flushing, chills, tremor, myoclonus, fever, and elevated CPK levels. The child responded to physostigmine infusion (total dose of 2 mg) with an appropriate reduction of heart rate and temperature (Kaminski et al, 1994). c) CASE REPORT: Serotonin syndrome was reported in a 5-year-old girl 4 hours following the ingestion of at least 400 mg sertraline. On admission to the ED, she was febrile (temperature 39.1 degrees C), diaphoretic, tachycardic (heart rate 177 bpm), hypertensive (blood pressure 158/90 mmHg), and tachypneic (24 breaths/min). 1) Three days after the ingestion, her serum sertraline level was 99 ng/mL, which decreased to 14 ng/mL 5 days later. During the week following the ingestion, the child experienced intermittent fevers, mild tachycardia, mild hypertension, mood swings, hyperactivity, and impulsive behavior. Symptoms resolved over 7 days, and she was discharged to her mother's care. Sertraline-induced serotonin syndrome was diagnosed (Pao & Tipnis, 1997).
d) CASE REPORT: Serotonin syndrome (dilated pupils, hyperactivity, hyperreflexia, unsteady ataxic gait, tremor, fever) was reported in a 24-month-old female child 12 hours after an ingestion of 10 sertraline 50 mg tablets (500 mg) . No other medications were ingested. Symptoms resolved 40 minutes after 1 dose of cyproheptadine 1 mg orally (Horowitz & Mullins, 1999). e) CASE REPORT: Following an intentional overdose of up to 8 g sertraline, with no coingestants, a 51-year-old woman was admitted to the ED. By day 3, the patient had acute mental status changes (agitation, disorientation, hallucinations), mydriasis, hypertension (blood pressure 150/115 mmHg), hyperthermia (101.4 degrees F), marked hyperreflexia, and sustained ankle clonus bilaterally but no muscle rigidity. CK level peaked at 9458 mcg/L. No seizures were noted. A primary diagnosis of serotonin syndrome was made. The patient recovered following symptomatic care (Brendel et al, 2000). 3.7.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) SEIZURES a) DOGS: Seizures were reported in single lethal high dose (80 mg/kg) animal studies in dogs that died on the first day of dosing (Davies & Klowe, 1998). In the same study, mice and rats exhibited hyperactivity following high dose sertraline.
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTRITIS 1) WITH THERAPEUTIC USE a) Infrequently, sertraline has been reported to cause constipation, indigestion, anorexia, flatulence, abdominal pain, and increased appetite (Cohn et al, 1990).
b) It may also be associated with eructation, dysphagia, incontinence, gastritis, glossitis, gum hyperplasia, hiccups, stomatitis, tenesmus, and tongue ulceration (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
B) DIARRHEA 1) WITH POISONING/EXPOSURE a) Diarrhea has been reported with sertraline doses of 200 mg and 400 mg (Reimherr et al, 1990; Saletu et al, 1986a). Intestinal motility was increased by excess serotonin.
b) CASE REPORT: An intentional overdose of sertraline 2 g in conjunction with alcohol in a 42-year-old woman caused diarrhea, without bleeding, which persisted for 12 hours. Her hospital course was, otherwise, uneventful. The diarrhea may have been exacerbated by sorbitol mixed with activated charcoal. (Brown & Kerr, 1994).
C) APTYALISM 1) WITH THERAPEUTIC USE a) Several studies have reported xerostomia as an occasional adverse effect of sertraline in therapeutic doses (Amin et al, 1989; Mattila et al, 1988; Reimherr et al, 1988).
D) VOMITING 1) WITH THERAPEUTIC USE a) Mild nausea and vomiting were noted 4 to 6 hours after single doses of 100 mg in one study, and were reported as a frequent side effect in another (Reimherr et al, 1990; Mattila et al, 1988).
2) WITH POISONING/EXPOSURE a) Vomiting has been reported in pediatric and adult overdoses of sertraline (Adson et al, 2001; Kaminski et al, 1994).
E) GASTROINTESTINAL HEMORRHAGE 1) WITH THERAPEUTIC USE a) In a retrospective cohort study (n=317,824 elderly patients), inhibition of serotonin reuptake by antidepressants, including sertraline, was found to increase the risk of upper gastrointestinal bleeding. With increasing inhibition of serotonin reuptake, the risk of bleeding increased by 10.7% and 9.8%, respectively, after controlling for age and previous gastrointestinal bleeding (van Walraven et al, 2001).
3.8.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) SALIVA INCREASED a) RATS: Marked salivation was reported in rats administered high dose sertraline orally (Davies & Klowe, 1998).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Asymptomatic elevations in serum transaminases have been reported within the first 9 weeks of sertraline treatment and have disappeared promptly upon discontinuation of the drug (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Elevated LDH, AST, and ALT levels were reported in a pediatric patient following an acute overdose. On the third hospital day, LDH was 862 U/L, AST 260 U/L, and ALT 198 U/L (Kaminski et al, 1994).
3.9.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) HEPATOCELLULAR DAMAGE a) Toxicity studies in the mouse, rat, and dog revealed the liver as the target organ for sertraline toxicity. At maximum tolerated doses, liver findings appeared to be consistent for hepatic xenobiotic-metabolizing enzyme induction. Findings included hepatomegaly, hepatocellular hypertrophy, increased serum transaminase activity, and proliferation of smooth endoplasmic reticulum. Hepatic steatosis was seen in mice and rats (Davies & Klowe, 1998).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) FINDING OF MENSTRUAL BLEEDING 1) WITH THERAPEUTIC USE a) Infrequent reports of dysmenorrhea, intermenstrual bleeding, amenorrhea, menorrhagia, leukorrhea, and atrophic vaginitis have occurred with therapy (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
B) URINARY SYMPTOMS 1) WITH THERAPEUTIC USE a) Urinary frequency, dysuria, urinary retention, urinary incontinence, and renal pain have occasionally been associated with sertraline therapy (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
C) ABNORMAL SEXUAL FUNCTION 1) WITH THERAPEUTIC USE a) Male sexual dysfunction, primarily delayed ejaculation, has been said to occur significantly more frequently with sertraline than with placebo (Doogan & Caillard, 1988).
D) PRIAPISM 1) WITH THERAPEUTIC USE a) Priapism has been reported rarely with therapy (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
b) Therapeutic use of sertraline 200 mg/day resulted in intermittent priapism in a 47-year-old man. Spontaneous resolution occurred after tapering the patient off sertraline. The patient was started on nefazodone treatment with no further episodes of priapism (Rand, 1998).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) PURPURIC DISORDER 1) WITH THERAPEUTIC USE a) HEMORRHAGE: Anterior chamber eye hemorrhage and purpura have occurred infrequently with sertraline therapeutic use (Prod Info Zoloft(R), sertraline, 2000).
b) Prolonged bleeding time and ecchymosis was observed in an adult receiving sertraline, which resolved spontaneously with drug cessation. Other laboratory studies were within normal limits (ie, prothrombin and partial thromboplastin time and hepatic enzymes). (Calhoun & Calhoun, 1996).
B) LEUKOCYTOSIS 1) WITH POISONING/OVERDOSE a) CASE REPORT: Leukocytosis of 24.5 x 10(9)/L was observed 9 hours following an overdose in a pediatric patient. It is likely that the leukocytosis was not directly related to the overdose, as a subsequent urine culture revealed greater than 100,000 lactose-fermenting Gram-negative rods (Kaminski et al, 1994).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) SKIN FINDING 1) WITH THERAPEUTIC USE a) Infrequently, rash, acne, pruritus, alopecia, hypertrichosis, dermatitis, erythema multiforme, urticaria, and skin discoloration have been reported.
B) VASODILATATION 1) WITH POISONING/EXPOSURE a) CASE REPORT: Vasodilation, with flushing, has been reported following an overdose of sertraline 2 g in a 42-year-old woman with concomitant alcohol ingestion (Brown & Kerr, 1994).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) MUSCULOSKELETAL FINDING 1) WITH THERAPEUTIC USE a) Sertraline has been associated with myalgia, arthralgia, dystonia, and muscle weakness (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008).
B) ENZYMES/SPECIFIC PROTEIN LEVELS - FINDING 1) WITH POISONING/EXPOSURE a) CASE REPORT: Elevated CPK levels were seen in a pediatric overdose of sertraline. CPK levels rose from 525 U/L on day 1 to 21,285 U/L on day 2, then gradually decreased over the following day (Kaminski et al, 1994).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) GYNECOMASTIA 1) WITH THERAPEUTIC USE a) Gynecomastia, galactorrhea, breast pain, and breast enlargement have been reported infrequently with sertraline use (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008; Bronzo & Stahl, 1993).
B) HYPOGLYCEMIA 1) WITH THERAPEUTIC USE a) Hypoglycemia has been reported rarely with therapy (Prod Info ZOLOFT(R) oral tablets, concentrate, 2008). 1) CASE REPORT: Hypoglycemia was reported in an 82-year-old nondiabetic woman 25 days after the initiation of sertraline therapy. Recurrent episodes occurred despite repeated administration of glucose. After sertraline therapy was stopped, but all other medications continued except furosemide, the hypoglycemic episodes ceased (Pollak et al, 2001).
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Reproductive |
3.20.1) SUMMARY
A) Sertraline has been classified as FDA Pregnancy Category C. A population-based study found no increased risk of malformations, but the exposed infants were more likely to require treatment in a special or intensive care unit. The use of SSRIs, including sertraline, after 20 weeks of gestation has been associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). In a clinical study from Sweden, an increased risk of PPHN was reported in infants exposed to SSRIs during both the early and later stages of pregnancy. Except for clubfoot, there was no significant association between the use of SSRIs in early pregnancy and the risks of birth defects, including congenital heart defects, according to a later population-based case-control study. An increased risk for social-behavioral abnormalities at 2 to 6 years of age was reported in children exposed to SSRIs or SNRIs in utero who developed neonatal abstinence syndrome (NAS) at birth.
3.20.2) TERATOGENICITY
A) CONGENITAL MALFORMATIONS 1) In a population-wide cohort study, sertraline use during the first trimester of pregnancy was associated with an increased risk of infants developing atrial and/or ventricular defects and craniosynostosis. When adjusted for potential confounders, sertraline use during the first trimester of pregnancy was not associated with a statistically significant overall risk of major congenital malformations compared with nonuse of antidepressants; however, an increased risk of atrial and/or ventricular defects and craniosynostosis was associated with first trimester sertraline exposure. In addition, exposure to selective serotonin reuptake inhibitors other than sertraline during the first trimester of pregnancy was also associated with an increased risk of craniosynostosis, as well as musculoskeletal defects suggesting an SSRI class effect (Berard et al, 2015).
2) Data from the case-controlled National Birth Defects Prevention Study (NBDPS), which included data from 13,714 infants born between 1997 and 2002, indicated that early maternal exposure (defined as treatment with any SSRI from 1 month before to 3 months after conception) to SSRIs was associated with anencephaly in 9 exposed infants out of 214 (significant 104% increased risk), craniosynostosis in 24 exposed infants out of 432 (significant 150% increased risk), and omphalocele in 11 exposed infants out of 181 (significant 180% increased risk). However, early exposure did not significantly increase the risks of congenital heart defects or most other birth defects. The most commonly used SSRIs reported by control mothers were sertraline, fluoxetine, paroxetine, and citalopram (Alwan et al, 2007).
3) SSRI administration lasting more than 30 days during the second or third lunar month of pregnancy was associated with a significant 80% increased risk of clubfoot occurrence in infants. Escitalopram administration had a significant 190% increased risk, paroxetine administration had a nonsignificant 820% increased risk, sertraline administration had a nonsignificant 60% increased risk, fluoxetine administration had a nonsignificant 30% increased risk, and citalopram administration had a nonsignificant 10% decreased risk. Because of small numbers of subjects exposed to these SSRIs, the estimated odds ratios were unstable for these agents, especially for paroxetine (Yazdy et al, 2014).
B) LACK OF EFFECT 1) ANIMAL STUDIES: Sertraline is reported to have no teratogenic effects in animals at maternally toxic doses. Similar to other serotonin reuptake inhibitors, decreased neonatal survival and growth was observed in these studies (Davies & Klowe, 1998).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Sertraline has been classified as FDA Pregnancy Category C (Prod Info ZOLOFT(R) tablets, oral concentrated solution, 2011).
B) PPHN 1) In a clinical study of 831,234 infants born between 1997 and 2005 in Sweden, the risk of persistent pulmonary hypertension of the newborn (PPHN) was increased by a significant 140% and was clearly associated with maternal use of SSRIs during early pregnancy. Maternal use of combination SSRIs during early pregnancy and antenatal use later in the pregnancy, was associated with a significant 260% increase in PPHN risk (Prod Info ZOLOFT(R) tablets, oral concentrated solution, 2011).
2) A case-control study found that the use of selective serotonin reuptake inhibitors (SSRIs) after 20 weeks of gestation was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). Fluoxetine, paroxetine, and sertraline were the specific SSRIs studied to carry this increased risk. A total of 377 women who had infants with PPHN were matched to 836 women and their infants. Assessment of exposure was determined by telephone interview within 6 months of birth. After adjusting for other covariates, SSRI use after 20 weeks of gestation was associated with a significant increased risk of 510% of delivering an infant with PPHN relative to no use during the pregnancy. SSRI use before 20 weeks of gestation and non-SSRI antidepressants use at any gestation time was not associated with increased risk of PPHN development. The incidence of PPHN in the general population is about 0.1 to 0.2%. According to this study, infants exposed to SSRIs after 20 weeks of gestation have a PPHN incidence of 0.6 to 1.2% (Chambers et al, 2006).
C) SPONTANEOUS ABORTION 1) A nested case-controlled study showed that sertraline, fluoxetine, citalopram, fluvoxamine, or combined use of 2 or more SSRIs during pregnancy did not correspond with a significantly increased risk of spontaneous abortion. However, paroxetine or venlafaxine use alone did increase the spontaneous abortion risk. Data collected from the Quebec Pregnancy Registry between January 1998 and December 2003 on women who filled at least 1 antidepressant prescription during pregnancy and had a clinically detected spontaneous abortion by the twentieth week of gestation (n=284) showed a significant 68% increase in risk of spontaneous abortion when compared with randomly selected registry controls (4 matched controls per case) without antidepressant use. Tracked antidepressant categories included SSRIs, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, combined use of 2 or more antidepressant classes, or others. Paroxetine use (significant 75% increased risk) or venlafaxine use (significant 111% increased risk) alone were independently associated with a higher risk of spontaneous abortion. The highest daily doses of paroxetine or venlafaxine during pregnancy were associated with the greatest spontaneous abortion risk; of the women taking paroxetine (n=84) or venlafaxine (n=33) who spontaneously aborted, an adjusted analysis showed 25.5% averaged daily doses of more than 25 mg of paroxetine and 50% averaged daily doses greater than 150 mg of venlafaxine (Nakhai-Pour et al, 2010).
D) LONG TERM NEURODEVELOPMENT 1) In a prospective, single-blind, cohort study, full-term infants who developed neonatal abstinence syndrome (NAS) at birth had similar cognitive abilities compared with full term infants without NAS at birth when reevaluated at 2 to 6 years of age. However, infants with NAS at birth were at an increased risk for social-behavioral abnormalities at 2 to 6 years of age. The study was designed to assess the long-term neurodevelopment of children exposed in utero to fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine, or venlafaxine. Children with NAS at birth (n=30; Finnegan score of 4 or greater) were compared to children without NAS (n=52; Finnegan score 0 to 3); both groups were similar in mean cognitive ability (106.9 +/- 14 versus 100.5 +/- 14.6, respectively; p=0.12) and developmental scores (98.9 +/- 11.4 versus 95.7 +/- 9.9, respectively; p=0.21). Cognitive ability was based on scores from the Wechsler Preschool and Primary Scale of Intelligence II, the Stanford-Binet Intelligence Scales, or the Bayley Scale of Infant Development II. The NAS infants had an increased risk of social-behavior abnormalities (significant 203% increased risk) based on the Denver Developmental Screening Test II (DDST-II) and NAS after birth was associated with advanced maternal age (12% increased risk). In addition, there was a trend towards small head circumference in the NAS group when compared with the children without NAS (n=6 (20%) versus n=3 (6%), respectively; p=0.068) (Klinger et al, 2011).
E) AUTISM SPECTRUM DISORDER 1) A cohort study of prospectively collected data demonstrated an increased risk of autism spectrum disorder (ASD) in children whose mothers used antidepressants during the second or third trimesters of pregnancy; the risk was even greater with second or third trimester exposure to SSRIs. Thirty-one infants who were exposed to antidepressants during the second or third trimester were diagnosed with ASD. After adjusting for potential confounders, second or third trimester exposure to antidepressants was associated with a significant 87% increased risk of ASD, while first trimester exposure or use of antidepressants in the year before pregnancy was not associated with any such risk. Use of SSRIs during the second or third trimester was associated with a significant more than 2-fold increased risk of ASD (22 exposed infants), while other classes of antidepressants were not associated with an increased risk. Even after restricting the sample size to those children whose mothers had a history of depression and used antidepressants during the second or third trimester, the risk of ASD still persisted. In addition, use of more than 1 class of antidepressants during the second or third trimester was associated with a significant more than 4-fold increased risk of ASD (Boukhris et al, 2016).
F) LACK OF EFFECT 1) In a prospective, multicenter, controlled cohort study of 267 pregnant women taking 3 different SSRIs, 147 women used sertraline at an average dose of 50 mg/day. When compared to the control group (267 pregnant women exposed only to nonteratogens) no differences between the two groups were reported with respect to occurrence of major fetal malformations, rate of miscarriage, stillbirth, prematurity, birth weight, and gestational age (Kulin et al, 1998).
2) A population-based study found no increased risk of malformations, but the exposed infants were more likely to require treatment in a special or intensive care unit (Malm et al, 2005).
3) A prospective study through the California Teratogen Information Service compared the outcomes of 112 pregnant women who took sertraline with 191 pregnant women not exposed to known teratogens. The rate of major anomalies in the two groups was similar (3.8% and 1.9%, respectively). Women taking sertraline during the third trimester more often delivered premature infants (16.3%) and their infants were more often admitted to the special care nursery (Chambers et al, 1999).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) SUMMARY: The selective serotonin-reuptake inhibitors, including sertraline, are lipid soluble and therefore excreted into breast milk (Baum & Misri, 1996). The American Academy of Pediatrics considers antidepressants to be drugs worthy of concern in the nursing infant (Anon, 2001). Serotonergic overstimulation has been reported in a breastfed preterm infant whose mother was taking sertraline during pregnancy and lactation (Muller et al, 2013). The manufacturer recommends that sertraline be administered to breastfeeding women with caution (Prod Info ZOLOFT(R) tablets, oral concentrated solution, 2011). If the decision is made to use sertraline, the infant should be monitored for anorexia, weight loss, irritability and insomnia.
2) According to a meta-analysis including studies of SRI use in lactating women, paroxetine and sertraline had better safety profiles than other SRIs. A daily dose of sertraline 25 to 300 mg resulted in a relative infant dose ranging from 0.54% to 2.2% (below the recommended safety limit). Detectable serum levels of sertraline (SR) were found in 10 out of 279 infants and norsertraline (NSR) was detected in 27 infants. Milk dosing concentrations were found in 62 infants (SER, 8.4 to 4640 ng/mL; NSER, 15 to 7897 mg/mL). The milk to plasma ratio for SER and NSER ranged from 0.42 to 4.81. Sertraline did not affect neurodevelopment and no long-term adverse effects were reported. Because sertraline has a better safety profile compared to other SSRIs, it should be preferred when treating a breastfeeding woman (Orsolini & Bellantuono, 2015).
3) In one study, serum levels were not detected in breastfed infants (n=6) of sertraline-treated mothers (Berle et al, 2004).
4) Sertraline and norsertraline plasma levels were measured in 3 mother-infant pairs, with maternal doses ranging from 50 to 100 mg/day. Sertraline plasma levels in the infants were low, less than 2 nanograms (ng)/mL of either sertraline or norsertraline. The infants showed no adverse effects (Mammen et al, 1997). Wisner et al (1998) reported sertraline and N-desmethylsertraline levels in 9 mother-infant pairs (Wisner et al, 1998). Sertraline levels were less than 2 ng/mL in 7 of the infants, and the metabolite levels were also low, less than or equal to 6 ng/mL, in 7 of the infants.
5) Two studies measured platelet 5-hydroxytryptamine levels in sertraline-treated mothers and their nursing infants before and after 6 to 16 weeks of maternal treatment with sertraline . Marked declines were noted in the mothers (to 10.2 +/- 2.9% of baseline), but little or no change in levels was reported in the infants. This is consistent with low plasma concentration of sertraline in the nursing infants (Epperson et al, 2001; Epperson et al, 1997).
6) CASE REPORT: Serotonergic overstimulation was reported in a breastfed preterm infant whose mother was taking sertraline during pregnancy and lactation. The infant developed hyperthermia and muscle tone regulation disorders such as muscular hypertonia, shivering, myoclonus, and tremor, as well as irritability and high-pitched crying. The symptoms were initially attributed to neonatal abstinence syndrome; however after symptoms continued, the mother discontinued breastfeeding on day 9 and the infant began to thrive and developed normally (Muller et al, 2013).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) A decrease in fertility was observed in 1 of 2 studies in animals that received 80 mg/kg of sertraline per day (4 times the MRHD on a mg/m(2) basis) (Prod Info ZOLOFT(R) tablets, oral concentrated solution, 2011).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential in humans.
3.21.4) ANIMAL STUDIES
A) BENIGN TUMORS 1) A dose-related increase in liver adenomas were observed in CD-1 male mice receiving sertraline 10 to 40 mg/kg (0.25 to 1 times the maximum recommended human dose [MRHD] on a mg/m(2) basis). No evidence for an increase was observed in CD-1 female mice or Long Evans rats of either sex receiving the same treatments, nor was there an increased incidence in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse, and this is of unknown significance to humans (Prod Info ZOLOFT(R) oral tablets, concentrate, 2009).
2) Follicular adenomas of the thyroid were also observed in female rats receiving sertraline 40 mg/kg (2 times the MRHD on a mg/m(2) basis) but was not accompanied by thyroid hyperplasia (Prod Info ZOLOFT(R) oral tablets, concentrate, 2009).
B) UTERINE ADENOCARCINOMAS 1) An increase in uterine adenocarcinomas in rats receiving sertraline 10 to 40 mg/kg (2 times the maximum recommended human dose on a mg/m(2) basis) was observed; however, compared with placebo controls, this effect was not clearly related to the drug (Prod Info ZOLOFT(R) oral tablets, concentrate, 2009).
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Genotoxicity |
A) No genotoxicity was observed, with or without metabolic activation, based on the bacterial mutation assay, mouse lymphoma mammalian cell mutation assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes (Prod Info ZOLOFT(R) oral tablets, concentrate, 2009).
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