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ZOLOFT (sertraline hydrochloride) Warnings And Precautions

Warnings And Precautions

POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

  • Pediatrics: Placebo-Controlled Clinical Trial Data:
    Recent analyses of placebo-controlled clinical trial safety databases from SSRI and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioral and emotional changes, including an increased risk of suicidal ideation and behavior over that of placebo.
  • The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.
  • Adults and Pediatrics: Additional data:
    There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type adverse events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behavior is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioral changes.

An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo.

Families and caregivers of patients being treated with ZOLOFT should be alerted about the need to monitor patients for the emergence of agitation, anxiety, panic attacks, hostility, irritability, hypomania or mania, unusual changes in behaviour, and other symptoms, as well as the emergence of suicidality particularly within several weeks of starting treatment or changing the dose. Such symptoms should be reported immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

Discontinuation Symptoms:

Patients currently taking ZOLOFT should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS.

Bone Fracture Risk:

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with ZOLOFT. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including ZOLOFT, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

Abnormal Bleeding:

SSRIs and SNRIs, including ZOLOFT, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of ZOLOFT and NSAIDs, ASA or other drugs that affect coagulation (see DRUG INTERACTIONS, Drugs Affecting Platelet Function). Caution is also advised in patients with a history of bleeding disorders or predisposing conditions (e.g., thrombocytopenia).

Activation of Mania/Hypomania:

During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of ZOLOFT (sertraline hydrochloride) treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants.

Akathisia

The use of sertraline has been associated with the development of akathisia (psychomotor restlessness), characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Carcinogenesis:

In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown.

Cardiovascular:

ZOLOFT has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. However, the electrocardiograms of 1006 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate that ZOLOFT is not associated with the development of clinically significant ECG abnormalities.

In placebo-controlled trials, the frequency of clinically noticeable changes (±15-20 mmHg) in blood pressure was similar in patients treated with either ZOLOFT or placebo.

QTc Prolongation/Torsade de Pointes

Sertraline has been demonstrated to cause a concentration-dependent prolongation of the QTc interval (see ADVERSE REACTIONS, Cardiac Electrophysiology). Cases of QTc prolongation and torsade de pointes have been reported during post-marketing use of sertraline, including at therapeutic doses.

Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.

The majority of reports occurred in patients with other risk factors such as concomitant illness, concomitant medications known to cause electrolyte imbalance or increase QT interval, and overdose.

Caution should be exercised when sertraline is prescribed in patients with an increased risk of QT prolongation including but not limited to those who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug, or in patients with cardiovascular disease or family history of QT prolongation, or in patients taking medicines known to increase QT interval, especially for patients with increased risk of QT prolongation (see DRUG INTERACTIONS, OVERDOSAGE).

Risk factors for torsade de pointes in the general population include, but are not limited to, the following: female gender; age 65 years or older; baseline prolongation of the QT/QTc interval; presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease); history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation); electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) or conditions that can lead to electrolyte disturbances (e.g., eating disorders); bradycardia (<50 beats per minute); acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma); diabetes mellitus; autonomic neuropathy.

When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.

Diabetes/Loss of Glycemic Control:

Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including ZOLOFT. Loss of glycemic control including both hyperglycemia and hypoglycemia has also been reported in patients with and without pre-existing diabetes. Patients should therefore be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycemic drug may need to be adjusted.

Discontinuation of Treatment with ZOLOFT:

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see ADVERSE REACTIONS). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response - see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Electroconvulsive Therapy:

There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and ZOLOFT.

Hepatic Dysfunction:

ZOLOFT is extensively metabolized by the liver. A single dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and increased AUC in comparison to normal subjects. The effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied. The use of ZOLOFT in patients with hepatic disease must be approached with caution. If ZOLOFT is administered to patients with hepatic impairment, a lower or less frequent dose should be considered - see ACTION and DOSAGE AND ADMINISTRATION).

Hyponatremia:

Hyponatremia may occur as a result of treatment with SSRIs or SNRIs including sertraline. In many cases, hyponatremia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also patients taking diuretics or who are otherwise volume-depleted may be at greater risk (see Use in Elderly). Several cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Discontinuation of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Microsomal Enzyme Induction:

ZOLOFT was shown to induce hepatic enzymes as determined by the decrease of the antipyrine half-life. This degree of induction reflects a clinically insignificant change in hepatic metabolism.

Occupational Hazards:

Any psychoactive drug may impair judgement, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.

Ophthalmologic:

Angle-Closure Glaucoma

As with other antidepressants, ZOLOFT can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

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 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).

Platelet Function:

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking ZOLOFT. While there have been reports of abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT had a causative role (see PRECAUTIONS, Abnormal Bleeding).

Renal Dysfunction:

ZOLOFT is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. In patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min) or moderate to severe renal impairment (creatinine clearance 10-29 ml/min), multiple-dose pharmacokinetic parameters (AUC0-24 or Cmax) were not significantly different compared with controls. Half-lives were similar and there were no differences in plasma protein binding in all groups studied. This study indicates that, as expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment.

Serotonin Syndrome/Neuroleptic Malignant Syndrome:

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of ZOLOFT®, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs and other dopamine antagonists. As these syndromes may result in potentially life-threatening conditions, treatment with ZOLOFT® should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome ZOLOFT® should not be used in combination with MAO inhibitors (including the antibiotic linezolid and methylthioninium chloride (methylene blue)) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution and avoided whenever possible in patients receiving other serotonergic drugs (amphetamines, triptans, fenfluramine, lithium, tramadol, St. John’s Wort (Hypericum perforatum), most tricyclic antidepressants, other antidepressants, and fentanyl), neuroleptics/antipsychotics or other antidopaminergic agents (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Seizure:

ZOLOFT has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with ZOLOFT in the development program for depression. However, 4 patients out of approximately 1800 (220 < 18 years of age) exposed during the development program for obsessive-compulsive disorder 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. Accordingly, ZOLOFT should be introduced with care in patients with a seizure disorder and should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. ZOLOFT should be discontinued in any patient who develops seizures.

Sexual Dysfunction:

Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction (see ADVERSE REACTIONS). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.

Suicide:

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. It should be noted that a causal role for SSRIs and other newer anti-depressants in inducing self-harm or harm to others has not been established. In order to minimize the opportunity for overdosage, prescriptions for ZOLOFT should be written for the smallest quantity of drug consistent with good patient management - see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Because of the well-established co-morbidity between both obsessive-compulsive disorder and depression and panic disorder and depression, the same precautions should be observed when treating patients with obsessive-compulsive disorder and panic disorder.

SPECIAL POPULATIONS

Male Fertility

Animal data have shown that some SSRIs may affect sperm quality. In human case reports, some reversible changes in sperm quality have been reported with some SSRIs. An impact on human fertility has not been observed.

Use in Pregnancy and Nursing Mothers:

The safety of ZOLOFT during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs "in early pregnancy" and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs "in early pregnancy" and an antenatal SSRI prescription "in later pregnancy."

Post-marketing reports indicate that some neonates exposed to ZOLOFT, SSRIs ( Selective Serotonin Reuptake Inhibitors ), or newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS Monoamine Oxidase Inhibitors). When treating a pregnant woman with ZOLOFT during the third trimester, the physician should carefully consider the potential risks and benefits of treatment - (see DOSAGE AND ADMINISTRATION).

Labor and Delivery:

The effect of ZOLOFT on labor and delivery in humans is unknown.

Use in Children:

The safety and effectiveness of ZOLOFT in children below the age of 18 have not been established and its use is not recommended.

Only limited clinical evidence is available concerning long-term safety data in children and adolescents, including effects on growth, sexual maturation and cognitive and behavioural developments (see TOXICOLOGY, Chronic Toxicity/Oncogenicity – Rat (juvenile animal study).

Use in Elderly:

462 elderly patients (> 65 years) with depressive illness have participated in multiple dose therapeutic studies with ZOLOFT. The pattern of adverse reactions in the elderly was comparable to that in younger patients.

SSRIS and SNRIs, including ZOLOFT, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk (see PRECAUTIONS, Hyponatremia).

Use in Patients with Concomitant Illness:

General: Clinical experience with ZOLOFT in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using ZOLOFT in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

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