DRUGS & SUPPLEMENTS

Petril Plus

Rating: 1 - 1 review(s)
advertisement
When are you taking this medicine?

Petril Plus uses

Petril Plus consists of Clonazepam, Escitalopram.

Clonazepam:


Pharmacological action

Petril Plus is an antiepileptic drugs from the group of benzodiazepine derivatives. This medication has a pronounced anticonvulsant and central muscle relaxant, anxiolytic, sedative and hypnotic effects.

Petril Plus (Clonazepam) strengthens the inhibitory effect of GABA on the transmission of nerve impulses.

Anxiolytic effects of this drug is due to the influence on the amygdaloid complex of the limbic system and appears in reducing the emotional stress, reduce anxiety, fear, anxiety.

The sedation effects is due to the influence on the reticular formation of the brainstem and nonspecific thalamic nucleus and manifests a decrease in neurotic symptoms (anxiety, fear).

Anticonvulsant effect is realized by increasing presynaptic inhibition.

The central muscle relaxant effect is due to inhibition of spinal polysynaptic afferent inhibitory ways (to a lesser extent and monosynaptic).

It is possibly and direct inhibition of motor nerves and muscle function.

Pharmacokinetics

For oral administration of Petril Plus (Clonazepam) its bioavailability is more than 90%. The plasma protein binding is more than 80%. Vd is 3.2 L / kg. T1/2 is 23 hours. This drug is excreted mainly as metabolites.

Why is Petril Plus prescribed?

As the medication of I row - epilepsy (adults, infants and young children): typical absence seizures (petit mal), atypical absence seizures (Lennox-Gastaut syndrome), nodding spasm, atonic seizures (a syndrome of "falling" or "drop-attacks").

As the medication of II row - infantile spasms (West syndrome).

As the medication of III row - tonic-clonic seizures (grand mal), simple and complex partial seizures and secondary generalized tonic-clonic seizures.

Status epilepticus (IV injections).

Somnambulism, muscular hypertonicity, insomnia (especially in patients with organic brain damage), psychomotor agitation, alcohol withdrawal syndrome (acute agitation, tremor, threatening or acute delirium tremens and hallucinations), panic disorder.

advertisement

Dosage and administration

Dosing regimen of Petril Plus is individual. For oral administration for adults the recommended initial dose is not more than 1 mg / day. The maintenance dose is 4-8 mg / day.

For infants and children aged 1-5 years, the initial dose should not exceed 250 micrograms / day, for children aged 5-12 years - 500 mcg / day. Supporting daily doses for children under 1 year are 0.5-1 mg, 1-5 years - 1-3 mg, 5-12 years - 3-6 mg.

For elderly patients the recommended starting dose is not exceeding 500 micrograms.

The daily dose should be divided into 3-4 equal doses. Maintenance doses prescribed in 2-3 weeks of treatment.

IV (slowly) for adults - 1 mg, for children under the age of 12 years - 500 mcg.

Petril Plus (Clonazepam) side effects, adverse reactions

CNS: early treatment - severe lethargy, fatigue, drowsiness, weakness, dizziness, stupor, headache; rarely - confusion, ataxia. When used in high doses, especially in long-term treatment - violation of articulation, diplopia, nystagmus, paradoxical reactions (including acute excitation states); anterograde amnesia. Rarely - hyperergic reactions, muscle weakness - depression. With long-term treatment of some forms of epilepsy may increase the frequency of seizures.

Digestive system: rarely - dry mouth, nausea, diarrhea, heartburn, nausea, vomiting, decreased appetite, constipation or diarrhea, liver damage, elevated liver transaminases and alkaline phosphatase, jaundice. In infants and young children may increase salivation.

Cardiovascular system: decreased blood pressure, tachycardia.

Endocrine: changes in libido, dysmenorrhea, reversible premature sexual development in children (part-time early puberty).

Respiratory system: with / in the introduction possible respiratory depression, particularly after treatment with other medicines that cause respiratory depression; in infants and young children it is possible bronchial hypersecretion.

Hematopoietic system: leukopenia, neutropenia, agranulocytosis, anemia, and thrombocytopenia.

Urinary system: urinary incontinence, urinary retention, impaired renal function.

Allergic reactions: hives, skin rash, itching, extremely rare - anaphylactic shock.

Dermatological reactions: transient alopecia, discoloration.

Other: addiction, drug dependence, with a sharp decrease in dose or cessation of reception - a withdrawal syndrome.

advertisement

Petril Plus contraindications

Inhibition of the respiratory center, severe COPD (the progression of the degree of respiratory failure), acute respiratory failure, myasthenia gravis, coma, shock, angle-closure glaucoma (acute attack or predisposition), acute alcohol intoxication with the weakening of the vital functions, acute poisoning with narcotic analgesics and hypnotics, severe depression (suicidal tendencies may occur), pregnancy, lactation, hypersensitivity to Petril Plus (Clonazepam).

Using during pregnancy and breastfeeding

Petril Plus is contraindicated for use during pregnancy and lactation. This medication crosses the placental barrier. Petril Plus (Clonazepam) may be excreted in breast milk.

Category effects on the fetus by FDA - D.

Special instructions

With caution used in patients with ataxia, severe liver disease, severe chronic respiratory failure, especially in the acute stage of deterioration, with episodes of sleep apnea.

With careful use in elderly patients because they may be slowed by removal of Petril Plus (Clonazepam) and reduced tolerance, especially in the presence of cardio-pulmonary insufficiency.

With prolonged use of this drug it may develop drug dependence. With a sharp lifting of Petril Plus (Clonazepam) after long-term treatment it may been developed the withdrawal syndrome.

In long-term use of Petril Plus (Clonazepam) in children should be kept in mind the possibility of side effects on physical and mental development, which may not manifest for years.

During the period of treatment avoid to drink alcohol.

During the period of treatment is observed slowing of psychomotor responses. It is necessary to take into account persons engaged in potentially hazardous activities that require attention and quickness of psychomotor reactions.

Petril Plus drug interactions

Simultaneous administration of Petril Plus (Clonazepam) with:

  • drugs providing a depressing effect on the CNS, ethanol, ethanol containing drugs may increase the CNS depressant effects.
  • Petril Plus (Clonazepam) enhances the action of muscle relaxants, with valproate sodium reducing sodium valproate and the provocation of seizures.
  • described the case to reduce the concentration of desipramine in plasma in 2 times and its increase after withdrawal of Petril Plus (Clonazepam).
  • carbamazepine which causes the induction of microsomal liver enzymes may increase metabolism and the resulting decrease in concentration of Petril Plus (Clonazepam) in plasma.
  • caffeine may reduce sedative and anxiolytic effects of Petril Plus (Clonazepam), with lamotrigine - may decrease the concentration of Petril Plus (Clonazepam) in plasma, with lithium carbonate - the development of neurotoxicity.
  • primidone increases its concentration in blood plasma, with tiapride - possibly the development of NMS.
  • toremifene it is possible significant reduction in AUC and T1/2 of toremifene in connection with the induction of liver enzymes under the influence of Petril Plus (Clonazepam) which leads to faster metabolism of toremifene.
  • may increase the concentration of phenytoin in blood plasma and the development of toxic reactions, its reduction or absence of these changes.
  • cimetidine increases the side effects of the CNS, however, the frequency of seizures in some patients decreased. There was described a case of headache with localization in the occipital region, while the application with phenelzine.

    Petril Plus in case of emergency / overdose

    Symptoms: CNS depression of varying severity (from lethargy to coma): severe drowsiness, prolonged confusion, depression of reflexes, coma, possible respiratory depression.

    Treatment: induction of vomiting and the prescription of activated charcoal (if the patient is conscious), gastric lavage through a tube (if patient is unconscious), symptomatic therapy, monitoring of vital functions (breathing, pulse, blood pressure), in intravenous fluids (to increase urine output), if necessary, mechanical ventilation. As a specific antidote may be used benzodiazepine receptor antagonist flumazenil (in hospital), however, flumazenil is not indicated for use in patients with epilepsy (likely provocation of epileptic seizures).

  • Escitalopram:


    1 INDICATIONS AND USAGE

    Petril Plus tablets are a selective serotonin reuptake inhibitor (SSRI) indicated for:

    • Acute and Maintenance Treatment of Major Depressive Disorder (MDD) in adults and adolescents aged 12 to 17 years (1.1)
    • Acute Treatment of Generalized Anxiety Disorder (GAD) in adults (1.2)

    1.1 Major Depressive Disorder

    Petril Plus (Escitalopram) tablets are indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [see Clinical Studies (14.1)].

    A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

    1.2 Generalized Anxiety Disorder

    Petril Plus (Escitalopram) tablets are indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults [see Clinical Studies (14.2)].

    Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.

    advertisement

    2 DOSAGE AND ADMINISTRATION

    Petril Plus tablets should be administered once daily, in the morning or evening, with or without food.

    Petril Plus (Escitalopram) tablets should generally be administered once daily, morning or evening with or without food (2.1, 2.2).


    Indication


    Recommended Dose


    MDD (2.1)


    Adolescents (2.1)


    Initial: 10 mg once daily

    Recommended: 10 mg once daily

    Maximum: 20 mg once daily


    Adults (2.1)


    Initial: 10 mg once daily

    Recommended: 10 mg once daily

    Maximum: 20 mg once daily


    GAD (2.2)


    Adults (2.2)


    Initial: 10 mg once daily

    Recommended: 10 mg once daily

    • No additional benefits seen at 20 mg/day dose (2.1).
    • 10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment (2.3).
    • No dosage adjustment for patients with mild or moderate renal impairment. Use caution in patients with severe renal impairment (2.3).
    • Discontinuing Petril Plus (Escitalopram) tablets: A gradual dose reduction is recommended (2.4).

    2.1 Major Depressive Disorder

    Initial Treatment

    Adolescents

    The recommended dose of Petril Plus (Escitalopram) tablets is 10 mg once daily. A flexible-dose trial of Petril Plus (Escitalopram) tablets (10 to 20 mg/day) demonstrated the effectiveness of Petril Plus (Escitalopram) tablets [see Clinical Studies (14.1)]. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.

    Adults

    The recommended dose of Petril Plus (Escitalopram) tablets is 10 mg once daily. A fixed-dose trial of Petril Plus (Escitalopram) tablets demonstrated the effectiveness of both 10 mg and 20 mg of Petril Plus (Escitalopram) tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg [see Clinical Studies (14.1)]. If the dose is increased to 20 mg, this should occur after a minimum of one week.

    Maintenance Treatment

    It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing Petril Plus (Escitalopram) tablets 10 or 20 mg/day in adult patients with major depressive disorder who responded while taking Petril Plus (Escitalopram) tablets during an 8 week, acute-treatment phase demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.1 )]. Nevertheless, the physician who elects to use Petril Plus (Escitalopram) tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.

    2.2 Generalized Anxiety Disorder

    Initial Treatment

    Adults

    The recommended starting dose of Petril Plus tablets is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

    Maintenance Treatment

    Generalized anxiety disorder is recognized as a chronic condition. The efficacy of Petril Plus (Escitalopram) tablets in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use Petril Plus (Escitalopram) tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

    2.3 Special Populations

    10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment.

    No dosage adjustment is necessary for patients with mild or moderate renal impairment. Petril Plus (Escitalopram) tablets should be used with caution in patients with severe renal impairment.

    2.4 Discontinuation of Treatment With Petril Plus Tablets

    Symptoms associated with discontinuation of Petril Plus (Escitalopram) tablets and other SSRIs and SNRIs have been reported [see Warnings and Precautions (5.3)]. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

    2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor Intended to Treat Psychiatric Disorders

    At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Petril Plus (Escitalopram) tablets. Conversely, at least 14 days should be allowed after stopping Petril Plus (Escitalopram) tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

    2.6 Use of Petril Plus Tablets With Other MAOIs Such as Linezolid or Methylene Blue

    Do not start Petril Plus (Escitalopram) tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4.1)].

    In some cases, a patient already receiving Petril Plus (Escitalopram) tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Petril Plus (Escitalopram) tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Petril Plus (Escitalopram) tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue .

    The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Petril Plus (Escitalopram) tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use .

    advertisement

    3 DOSAGE FORMS AND STRENGTHS

    Petril Plus (Escitalopram) tablets are film-coated, round tablets containing Petril Plus (Escitalopram) oxalate in strengths equivalent to 5 mg, 10 mg and 20 mg Petril Plus (Escitalopram) base. The 10 and 20 mg tablets are scored. The 5 mg tablet is debossed with “5850” on one side and “Ivax hourglass logo” and “5” on the other. The 10 mg tablet is debossed with “5851” on one side and “Ivax hourglass logo” and “10” on the other. The 20 mg tablet is debossed with “5852” on one side and “Ivax hourglass logo” and “20” on the other.

    • Tablets: 5 mg, 10 mg (scored) and 20 mg (scored) (3)

    4 CONTRAINDICATIONS

    • Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with Petril Plus or within 14 days of stopping treatment with Petril Plus (Escitalopram). Do not use Petril Plus (Escitalopram) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Petril Plus (Escitalopram) in a patient who is being treated with linezolid or intravenous methylene blue (4.1).
    • Pimozide: Do not use concomitantly (4.2).
    • Known hypersensitivity to Petril Plus (Escitalopram) or citalopram or any of the inactive ingredients (4.3).

    4.1 Monoamine Oxidase Inhibitors (MAOIs)

    The use of MAOIs intended to treat psychiatric disorders with Petril Plus (Escitalopram) tablets or within 14 days of stopping treatment with Petril Plus (Escitalopram) tablets is contraindicated because of an increased risk of serotonin syndrome. The use of Petril Plus (Escitalopram) tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5), and Warnings and Precautions (5.2)].

    Starting Petril Plus (Escitalopram) tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6), and Warnings and Precautions (5.2)].

    4.2 Pimozide

    Concomitant use in patients taking pimozide is contraindicated [see Drug Interactions ].

    4.3 Hypersensitivity to Petril Plus (Escitalopram) or Citalopram

    Petril Plus (Escitalopram) tablets are contraindicated in patients with a hypersensitivity to Petril Plus (Escitalopram) or citalopram or any of the inactive ingredients in Petril Plus (Escitalopram) tablets.

    5 WARNINGS AND PRECAUTIONS

    • Clinical Worsening/Suicide Risk: Monitor for clinical worsening, suicidality and unusual change in behavior, especially during the initial few months of therapy or at times of dose changes.
    • Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including Petril Plus (Escitalopram), both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue Petril Plus (Escitalopram) and initiate supportive treatment. If concomitant use of Petril Plus (Escitalopram) with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2).
    • Discontinuation of Treatment with Petril Plus (Escitalopram): A gradual reduction in dose rather than abrupt cessation is recommended whenever possible (5.3).
    • Seizures: Prescribe with care in patients with a history of seizure (5.4).
    • Activation of Mania/Hypomania: Use cautiously in patients with a history of mania (5.5).
    • Hyponatremia: Can occur in association with SIADH (5.6).
    • Abnormal Bleeding: Use caution in concomitant use with NSAIDs, aspirin, warfarin or other drugs that affect coagulation (5.7).
    • Interference with Cognitive and Motor Performance: Use caution when operating machinery (5.8).
    • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9)
    • Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses (5.10).

    5.1 Clinical Worsening and Suicide Risk

    Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

    The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 .


    Age Range


    Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated


    Increases Compared to Placebo


    < 18


    14 additional cases


    18 to 24


    5 additional cases


    Decreases Compared to Placebo


    25 to 64


    1 fewer case


    ≥ 65


    6 fewer cases


    No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

    It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

    All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

    The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

    Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

    If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4)].

    Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers [see also Patient Counseling Information (17.1)]. Prescriptions for Petril Plus (Escitalopram) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

    Screening Patients for Bipolar Disorder

    A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Petril Plus (Escitalopram) is not approved for use in treating bipolar depression.

    5.2 Serotonin Syndrome

    The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Petril Plus, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

    Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination) seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

    The concomitant use of Petril Plus (Escitalopram) with MAOIs intended to treat psychiatric disorders is contraindicated. Petril Plus (Escitalopram) should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Petril Plus (Escitalopram). Petril Plus (Escitalopram) should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.5 and 2.6)].

    If concomitant use of Petril Plus (Escitalopram) with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

    Treatment with Petril Plus (Escitalopram) and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

    5.3 Discontinuation of Treatment With Petril Plus (Escitalopram)

    During marketing of Petril Plus (Escitalopram) and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

    Patients should be monitored for these symptoms when discontinuing treatment with Petril Plus (Escitalopram). A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4)].

    5.4 Seizures

    Although anticonvulsant effects of racemic citalopram have been observed in animal studies, Petril Plus has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of Petril Plus (Escitalopram), cases of convulsion have been reported in association with Petril Plus (Escitalopram) treatment. Like other drugs effective in the treatment of major depressive disorder, Petril Plus (Escitalopram) should be introduced with care in patients with a history of seizure disorder.

    5.5 Activation of Mania/Hypomania

    In placebo-controlled trials of Petril Plus (Escitalopram) in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with Petril Plus (Escitalopram) and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with Petril Plus (Escitalopram) treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Petril Plus (Escitalopram) should be used cautiously in patients with a history of mania.

    5.6 Hyponatremia

    Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Petril Plus. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Petril Plus (Escitalopram) was discontinued. Cases with serum sodium 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 Geriatric Use (8.5 )]. Discontinuation of Petril Plus (Escitalopram) 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.

    5.7 Abnormal Bleeding

    SSRIs and SNRIs, including Petril Plus (Escitalopram), may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the 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 Petril Plus (Escitalopram) and NSAIDs, aspirin, or other drugs that affect coagulation.

    5.8 Interference With Cognitive and Motor Performance

    In a study in normal volunteers, Petril Plus 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Petril Plus (Escitalopram) therapy does not affect their ability to engage in such activities.

    5.9 Angle Closure Glaucoma

    Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Petril Plus (Escitalopram) may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    5.10 Use in Patients With Concomitant Illness

    Clinical experience with Petril Plus (Escitalopram) in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Petril Plus (Escitalopram) in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

    Petril Plus (Escitalopram) has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

    In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Petril Plus (Escitalopram) in hepatically impaired patients is 10 mg/day [see Dosage and Administration (2.3)].

    Because Petril Plus (Escitalopram) is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Petril Plus (Escitalopram), however, it should be used with caution in such patients [see Dosage and Administration (2.3)].

    6 ADVERSE REACTIONS

    Most commonly observed adverse reactions are: insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia (6.1).

    To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

    6.1 Clinical Trials Experience

    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

    Clinical Trial Data Sources

    Pediatrics (6 to 17 years)

    Adverse events were collected in 576 pediatric patients (286 Petril Plus (Escitalopram), 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of Petril Plus (Escitalopram) in pediatric patients less than 12 years of age has not been established.

    Adults

    Adverse events information for Petril Plus (Escitalopram) was collected from 715 patients with major depressive disorder who were exposed to Petril Plus (Escitalopram) and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to Petril Plus (Escitalopram) in open-label trials. The adverse event information for Petril Plus (Escitalopram) in patients with GAD was collected from 429 patients exposed to Petril Plus (Escitalopram) and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.

    Adverse events during exposure were obtained primarily by general inquiry and 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 events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.

    The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

    Adverse Events Associated With Discontinuation of Treatment

    Major Depressive Disorder

    Pediatrics (6 to 17 years)

    Adverse events were associated with discontinuation of 3.5% of 286 patients receiving Petril Plus (Escitalopram) and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for Petril Plus (Escitalopram) and greater than placebo) associated with discontinuation was insomnia (1% Petril Plus (Escitalopram), 0% placebo).

    Adults

    Among the 715 depressed patients who received Petril Plus (Escitalopram) in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day Petril Plus (Escitalopram) was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day Petril Plus (Escitalopram) was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day Petril Plus (Escitalopram) (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Petril Plus (Escitalopram), and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

    Generalized Anxiety Disorder

    Adults

    Among the 429 GAD patients who received Petril Plus (Escitalopram) 10 to 20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with Petril Plus (Escitalopram), and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).

    Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials

    Major Depressive Disorder

    Pediatrics (6 to 17 years)

    The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2 . However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for Petril Plus (Escitalopram) and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

    Adults

    The most commonly observed adverse reactions in Petril Plus (Escitalopram) patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

    Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received Petril Plus (Escitalopram) at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Petril Plus (Escitalopram) and for which the incidence in patients treated with Petril Plus (Escitalopram) was greater than the incidence in placebo-treated patients.


    Treatment-Emergent Adverse Reactions observed with a frequency of 2% and greater than placebo for Major Depressive Disorder


    Adverse Reaction


    Petril Plus (Escitalopram)


    Placebo


    (N = 715)


    (N = 592)


    %


    %


    Autonomic Nervous System Disorders


    Dry Mouth


    6%


    5%


    Sweating Increased


    5%


    2%


    Central & Peripheral Nervous System Disorders


    Dizziness


    5%


    3%


    Gastrointestinal Disorders


    Nausea


    15%


    7%


    Diarrhea


    8%


    5%


    Constipation


    3%


    1%


    Indigestion


    3%


    1%


    Abdominal Pain


    2%


    1%


    General


    Influenza-like Symptoms


    5%


    4%


    Fatigue


    5%


    2%


    Psychiatric Disorders


    Insomnia


    9%


    4%


    Somnolence


    6%


    2%


    Appetite Decreased


    3%


    1%


    Libido Decreased


    3%


    1%


    Respiratory System Disorders


    Rhinitis


    5%


    4%


    Sinusitis


    3%


    2%


    Urogenital


    Ejaculation DisorderPrimarily ejaculatory delay. Denominator used was for males only (N = 225 Petril Plus (Escitalopram); N = 188 placebo).


    9%


    < 1%


    Impotence


    3%


    < 1%


    AnorgasmiaDenominator used was for females only (N = 490 Petril Plus (Escitalopram); N = 404 placebo).


    2%


    < 1%


    Generalized Anxiety Disorder

    Adults

    The most commonly observed adverse reactions in Petril Plus (Escitalopram) patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia.

    Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received Petril Plus (Escitalopram) 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Petril Plus (Escitalopram) and for which the incidence in patients treated with Petril Plus (Escitalopram) was greater than the incidence in placebo-treated patients.


    Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Generalized Anxiety Disorder


    Adverse Reactions


    Petril Plus (Escitalopram)


    Placebo


    (N = 429)


    (N = 427)


    %


    %


    Autonomic Nervous System Disorders


    Dry Mouth


    9%


    5%


    Sweating Increased


    4%


    1%


    Central & Peripheral Nervous System Disorders


    Headache


    24%


    17%


    Paresthesia


    2%


    1%


    Gastrointestinal Disorders


    Nausea


    18%


    8%


    Diarrhea


    8%


    6%


    Constipation


    5%


    4%


    Indigestion


    3%


    2%


    Vomiting


    3%


    1%


    Abdominal Pain


    2%


    1%


    Flatulence


    2%


    1%


    Toothache


    2%


    0%


    General


    Fatigue


    8%


    2%


    Influenza-like Symptoms


    5%


    4%


    Musculoskeletal System Disorder


    Neck/Shoulder Pain


    3%


    1%


    Psychiatric Disorders


    Somnolence


    13%


    7%


    Insomnia


    12%


    6%


    Libido Decreased


    7%


    2%


    Dreaming Abnormal


    3%


    2%


    Appetite Decreased


    3%


    1%


    Lethargy


    3%


    1%


    Respiratory System Disorders


    Yawning


    2%


    1%


    Urogenital


    Ejaculation DisorderPrimarily ejaculatory delay. Denominator used was for males only (N = 182 Petril Plus (Escitalopram); N = 195 placebo).


    14%


    2%


    AnorgasmiaDenominator used was for females only (N = 247 Petril Plus (Escitalopram); N = 232 placebo).


    6%


    < 1%


    Menstrual Disorder


    2%


    1%


    Dose Dependency of Adverse Reactions

    The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥ 5% in either the 10 mg or 20 mg Petril Plus (Escitalopram) groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg escitalopram-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day Petril Plus (Escitalopram) group with an incidence that was approximately twice that of the 10 mg/day Petril Plus (Escitalopram) group and approximately twice that of the placebo group.


    Incidence of Common Adverse Reactions in Patients with Major

    Depressive Disorder


    Adverse Reaction


    Placebo


    10 mg/day


    20 mg/day


    (N = 311)


    Petril Plus (Escitalopram)


    Petril Plus (Escitalopram)


    (N = 310)


    (N = 125)


    Insomnia


    4%


    7%


    14%


    Diarrhea


    5%


    6%


    14%


    Dry Mouth


    3%


    4%


    9%


    Somnolence


    1%


    4%


    9%


    Dizziness


    2%


    4%


    7%


    Sweating Increased


    < 1%


    3%


    8%


    Constipation


    1%


    3%


    6%


    Fatigue


    2%


    2%


    6%


    Indigestion


    1%


    2%


    6%



    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 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.


    Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials


    Adverse Event


    Petril Plus (Escitalopram)


    Placebo


    In Males Only


    (N = 407)


    (N = 383)


    Ejaculation Disorder

    (primarily ejaculatory delay)


    12%


    1%


    Libido Decreased


    6%


    2%


    Impotence


    2%


    < 1%


    In Females Only


    (N = 737)


    (N = 636)


    Libido Decreased


    3%


    1%


    Anorgasmia


    3%


    < 1%


    There are no adequately designed studies examining sexual dysfunction with Petril Plus (Escitalopram) 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.

    Vital Sign Changes

    Petril Plus (Escitalopram) and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with Petril Plus (Escitalopram) treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving Petril Plus (Escitalopram) indicated that Petril Plus (Escitalopram) treatment is not associated with orthostatic changes.

    Weight Changes

    Patients treated with Petril Plus (Escitalopram) in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.

    Laboratory Changes

    Petril Plus (Escitalopram) and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Petril Plus (Escitalopram) treatment.

    ECG Changes

    Electrocardiograms from Petril Plus (Escitalopram) (N = 625) and placebo (N = 527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the Petril Plus (Escitalopram) group had a QTcF interval > 500 msec or a prolongation > 60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the Petril Plus (Escitalopram) and the placebo group. The incidence of bradycardic outliers was 0.5% in the Petril Plus (Escitalopram) group and 0.2% in the placebo group.

    QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg Petril Plus (Escitalopram) given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Petril Plus (Escitalopram) 30 mg given once daily resulted in mean Cmax of 1.7 fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.

    Other Reactions Observed During the Premarketing Evaluation of Petril Plus (Escitalopram)

    Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with Petril Plus (Escitalopram) for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3 , those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the WARNINGS AND PRECAUTIONS section (5).

    Cardiovascular - hypertension, palpitation.

    Central and Peripheral Nervous System Disorders - light-headed feeling, migraine.

    Gastrointestinal Disorders - abdominal cramp, heartburn, gastroenteritis.

    General - allergy, chest pain, fever, hot flushes, pain in limb.

    Metabolic and Nutritional Disorders - increased weight.

    Musculoskeletal System Disorders - arthralgia, myalgia jaw stiffness.

    Psychiatric Disorders - appetite increased, concentration impaired, irritability.

    Reproductive Disorders/Female - menstrual cramps, menstrual disorder.

    Respiratory System Disorders - bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.

    Skin and Appendages Disorders - rash.

    Special Senses - vision blurred, tinnitus.

    Urinary System Disorders - urinary frequency, urinary tract infection.

    6.2 Postmarketing Experience

    Adverse Reactions Reported Subsequent to the Marketing of Petril Plus (Escitalopram)

    The following additional adverse reactions have been identified from spontaneous reports of Petril Plus (Escitalopram) received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Petril Plus (Escitalopram) and have not been listed elsewhere in labeling. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:

    Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia.

    Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia.

    Ear and labyrinth disorders: vertigo

    Endocrine Disorders: diabetes mellitus, hyperprolactinemia, SIADH.

    Eye Disorders: angle closure glaucoma, diplopia, mydriasis, visual disturbance.

    Gastrointestinal Disorder: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage.

    General Disorders and Administration Site Conditions: abnormal gait, asthenia, edema, fall, feeling abnormal, malaise.

    Hepatobiliary Disorders: fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis.

    Immune System Disorders: allergic reaction, anaphylaxis.

    Investigations: bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased.

    Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia, hypokalemia, hyponatremia.

    Musculoskeletal and Connective Tissue Disorders: muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis.

    Nervous System Disorders: akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor.

    Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion.

    Psychiatric Disorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency.

    Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention.

    Reproductive System and Breast Disorders: menorrhagia, priapism.

    Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn.

    Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson syndrome, toxic epidermal necrolysis, urticaria.

    Vascular Disorders: deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.

    7 DRUG INTERACTIONS

    Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended.

    Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) (7.6).

    7.1 Monoamine Oxidase Inhibitors (MAOIs)

    [See Dosage and Administration (2.5 and 2.6), Contraindications (4.1) and Warnings and Precautions (5.2)].

    7.2 Serotonergic Drugs

    [See Dosage and Administration, Contraindications (4.1) and Warnings and Precautions (5.2)].

    7.3 Triptans

    There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Petril Plus (Escitalopram) with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2)].

    7.4 CNS Drugs

    Given the primary CNS effects of Petril Plus, caution should be used when it is taken in combination with other centrally acting drugs.

    7.5 Alcohol

    Although Petril Plus (Escitalopram) did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking Petril Plus (Escitalopram) is not recommended.

    7.6 Drugs That Interfere With Hemostasis

    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 the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Petril Plus (Escitalopram) is initiated or discontinued.

    7.7 Cimetidine

    In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.

    7.8 Digoxin

    In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin did not significantly affect the pharmacokinetics of either citalopram or digoxin.

    7.9 Lithium

    Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of Petril Plus (Escitalopram), caution should be exercised when Petril Plus (Escitalopram) and lithium are coadministered.

    7.10 Pimozide and Celexa

    In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.

    7.11 Sumatriptan

    There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI ) is clinically warranted, appropriate observation of the patient is advised.

    7.12 Theophylline

    Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

    7.13 Warfarin

    Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

    7.14 Carbamazepine

    Combined administration of racemic citalopram and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of Petril Plus (Escitalopram) should be considered if the two drugs are coadministered.

    7.15 Triazolam

    Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

    7.16 Ketoconazole

    Combined administration of racemic citalopram and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

    7.17 Ritonavir

    Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and Petril Plus (Escitalopram) (20 mg) did not affect the pharmacokinetics of either ritonavir or Petril Plus (Escitalopram).

    7.18 CYP3A4 and -2C19 Inhibitors

    In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of Petril Plus. However, coadministration of Petril Plus (Escitalopram) (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of Petril Plus (Escitalopram). Because Petril Plus (Escitalopram) is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease Petril Plus (Escitalopram) clearance.

    7.19 Drugs Metabolized by Cytochrome P4502D6

    In vitro studies did not reveal an inhibitory effect of Petril Plus (Escitalopram) on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with Petril Plus (Escitalopram), of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on Petril Plus (Escitalopram) metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for Petril Plus (Escitalopram), i.e., coadministration of Petril Plus (Escitalopram) (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of Petril Plus (Escitalopram) and drugs metabolized by CYP2D6.

    7.20 Metoprolol

    Administration of 20 mg/day Petril Plus for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Petril Plus (Escitalopram) and metoprolol had no clinically significant effects on blood pressure or heart rate.

    7.21 Electroconvulsive Therapy (ECT)

    There are no clinical studies of the combined use of ECT and Petril Plus (Escitalopram).

    8 USE IN SPECIFIC POPULATIONS

    Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus.

    Nursing Mothers: Caution should be exercised when administered to a nursing woman (8.3).

    Pediatric Use: Safety and effectiveness of Petril Plus (Escitalopram) has not been established in pediatric MDD patients less than 12 years of age (8.4).

    8.1 Pregnancy

    Pregnancy Category C

    In a rat embryo/fetal development study, oral administration of Petril Plus (Escitalopram) (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately ≥ 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis).

    When female rats were treated with Petril Plus (Escitalopram) (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis.

    In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.

    In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.

    When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. A no-effect dose was not determined in that study.

    There are no adequate and well-controlled studies in pregnant women; therefore, Petril Plus (Escitalopram) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Pregnancy-Nonteratogenic Effects

    Neonates exposed to Petril Plus (Escitalopram) and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)].

    Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Petril Plus (Escitalopram)) in pregnancy and PPHN. Other studies do not show a significant statistical association.

    Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

    When treating a pregnant woman with Petril Plus (Escitalopram), the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [see Dosage and Administration (2.1)].

    8.2 Labor and Delivery

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

    8.3 Nursing Mothers

    Petril Plus (Escitalopram) is excreted in human breast milk. Limited data from women taking 10 to 20 mg Petril Plus (Escitalopram) showed that exclusively breastfed infants receive approximately 3.9% of the maternal weight-adjusted dose of Petril Plus (Escitalopram) and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when Petril Plus (Escitalopram) is administered to a nursing woman.

    8.4 Pediatric Use

    The safety and effectiveness of Petril Plus have been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [see Clinical Studies (14.1)]. Although maintenance efficacy in adolescent patients with major depressive disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of Petril Plus (Escitalopram) pharmacokinetic parameters in adults and adolescent patients.

    The safety and effectiveness of Petril Plus (Escitalopram) have not been established in pediatric (younger than 12 years of age) patients with major depressive disorder. In a 24-week, open-label safety study in 118 children (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for Petril Plus (Escitalopram).

    Safety and effectiveness of Petril Plus (Escitalopram) has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder.

    Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as Petril Plus (Escitalopram).

    8.5 Geriatric Use

    Approximately 6% of the 1144 patients receiving Petril Plus (Escitalopram) in controlled trials of Petril Plus (Escitalopram) in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of Petril Plus (Escitalopram) between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of Petril Plus (Escitalopram) cannot be ruled out.

    SSRIs and SNRIs, including Petril Plus (Escitalopram), have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Hyponatremia (5.6)].

    In two pharmacokinetic studies, Petril Plus (Escitalopram) half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged [see Clinical Pharmacology (12.3)]. 10 mg/day is the recommended dose for elderly patients [see Dosage and Administration (2.3)].

    Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.

    9 DRUG ABUSE AND DEPENDENCE

    9.2 Abuse and Dependence

    Physical and Psychological Dependence

    Animal studies suggest that the abuse liability of racemic citalopram is low. Petril Plus (Escitalopram) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with Petril Plus (Escitalopram) did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Petril Plus (Escitalopram) patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

    10 OVERDOSAGE

    10.1 Human Experience

    In clinical trials of Petril Plus, there were reports of Petril Plus (Escitalopram) overdose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation of Petril Plus (Escitalopram), Petril Plus (Escitalopram) overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of Petril Plus (Escitalopram) has been rarely reported.

    Symptoms most often accompanying Petril Plus (Escitalopram) overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.

    10.2 Management of Overdose

    Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of Petril Plus (Escitalopram), forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Petril Plus (Escitalopram).

    In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

    11 DESCRIPTION

    Petril Plus (Escitalopram) tablets USP are an orally administered selective serotonin reuptake inhibitor (SSRI). Petril Plus (Escitalopram) is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Petril Plus (Escitalopram) oxalate, USP, is designated S-(+)-1-[3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:

    • C20H21FN2O - C2H2O4 M.W. 414.43

    Petril Plus (Escitalopram) oxalate, USP, occurs as a fine, white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

    Petril Plus (Escitalopram) tablets USP are film-coated, round tablets containing Petril Plus (Escitalopram) oxalate, USP, in strengths equivalent to 5 mg, 10 mg, and 20 mg Petril Plus (Escitalopram) base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: corn starch, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

    structural formula

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The mechanism of antidepressant action of Petril Plus, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

    12.2 Pharmacodynamics

    In vitro and in vivo studies in animals suggest that Petril Plus (Escitalopram) is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Petril Plus (Escitalopram) is at least 100 fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with Petril Plus (Escitalopram). Petril Plus (Escitalopram) has no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. Petril Plus (Escitalopram) also does not bind to, or has low affinity for, various ion channels including Na+, K+, Cl-, and Ca++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.

    12.3 Pharmacokinetics

    The single- and multiple-dose pharmacokinetics of Petril Plus (Escitalopram) are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of Petril Plus (Escitalopram) is mainly hepatic, with a mean terminal half-life of about 27 to 32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of Petril Plus (Escitalopram) in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of Petril Plus (Escitalopram) are bioequivalent.

    Absorption and Distribution

    Following a single oral dose (20 mg tablet or solution) of Petril Plus (Escitalopram), peak blood levels occur at about 5 hours. Absorption of Petril Plus (Escitalopram) is not affected by food.

    The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on Petril Plus (Escitalopram) are unavailable.

    The binding of Petril Plus (Escitalopram) to human plasma proteins is approximately 56%.

    Metabolism and Elimination

    Following oral administrations of Petril Plus (Escitalopram), the fraction of drug recovered in the urine as Petril Plus (Escitalopram) and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of Petril Plus (Escitalopram) is 600 mL/min, with approximately 7% of that due to renal clearance.

    Petril Plus (Escitalopram) is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged Petril Plus (Escitalopram) is the predominant compound in plasma. At steady state, the concentration of the Petril Plus (Escitalopram) metabolite S-DCT in plasma is approximately one-third that of Petril Plus (Escitalopram). The level of S-DDCT was not detectable in most subjects. In vitro studies show that Petril Plus (Escitalopram) is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of Petril Plus (Escitalopram) do not contribute significantly to the antidepressant actions of Petril Plus (Escitalopram). S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels.

    In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of Petril Plus (Escitalopram).

    Population Subgroups

    Age

    Adolescents - In a single dose study of 10 mg Petril Plus (Escitalopram), AUC of Petril Plus (Escitalopram) decreased by 19%, and Cmax increased by 26% in healthy adolescent subjects (12 to 17 years of age) compared to adults. Following multiple dosing of 40 mg/day citalopram, Petril Plus (Escitalopram) elimination half-life, steady-state Cmax and AUC were similar in patients with MDD (12 to 17 years of age) compared to adult patients. No adjustment of dosage is needed in adolescent patients.

    Elderly - Petril Plus (Escitalopram) pharmacokinetics in subjects ≥ 65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Petril Plus (Escitalopram) AUC and half-life were increased by approximately 50% in elderly subjects, and Cmax was unchanged. 10 mg is the recommended dose for elderly patients [see Dosage and Administration (2.3)].

    Gender - Based on data from single- and multiple-dose studies measuring Petril Plus (Escitalopram) in elderly, young adults, and adolescents, no dosage adjustment on the basis of gender is needed.

    Reduced Hepatic Function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 10 mg is the recommended dose of Petril Plus (Escitalopram) for most hepatically impaired patients [see Dosage and Administration (2.3)].

    Reduced Renal Function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of Petril Plus (Escitalopram) in patients with severely reduced renal function (creatinine clearance < 20 mL/min).

    Drug-Drug Interactions

    In vitro enzyme inhibition data did not reveal an inhibitory effect of Petril Plus (Escitalopram) on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, Petril Plus (Escitalopram) would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that Petril Plus (Escitalopram), at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect. See Drug Interactions (7.18) for more detailed information on available drug interaction data.

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.

    Mutagenesis

    Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.

    Impairment of Fertility

    When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.

    13.2 Animal Toxicology and/or Pharmacology

    Retinal Changes in Rats

    Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2 year carcinogenicity study with racemic citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.

    Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.

    Cardiovascular Changes in Dogs

    In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.

    14 CLINICAL STUDIES

    14.1 Major Depressive Disorder

    Adolescents

    The efficacy of Petril Plus as an acute treatment for major depressive disorder in adolescent patients was established in an 8 week, flexible-dose, placebo-controlled study that compared Petril Plus (Escitalopram) 10 to 20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, Petril Plus (Escitalopram) showed statistically significant greater mean improvement compared to placebo on the CDRS-R.

    The efficacy of Petril Plus (Escitalopram) in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 to 40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup.

    Two additional flexible-dose, placebo-controlled MDD studies (one Petril Plus (Escitalopram) study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy.

    Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of Petril Plus (Escitalopram) pharmacokinetic parameters in adults and adolescent patients.

    Adults

    The efficacy of Petril Plus (Escitalopram) as a treatment for major depressive disorder was established in three, 8 week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder. The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS).

    A fixed-dose study compared 10 mg/day Petril Plus (Escitalopram) and 20 mg/day Petril Plus (Escitalopram) to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day Petril Plus (Escitalopram) treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg Petril Plus (Escitalopram) groups were similar on this outcome measure.

    In a second fixed-dose study of 10 mg/day Petril Plus (Escitalopram) and placebo, the 10 mg/day Petril Plus (Escitalopram) treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.

    In a flexible-dose study, comparing Petril Plus (Escitalopram), titrated between 10 and 20 mg/day, to placebo and citalopram, titrated between 20 and 40 mg/day, the Petril Plus (Escitalopram) treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.

    Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

    In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8 week, open-label treatment phase with Petril Plus (Escitalopram) 10 or 20 mg/day, were randomized to continuation of Petril Plus (Escitalopram) at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to ≤ 12. Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response. Patients receiving continued Petril Plus (Escitalopram) experienced a statistically significant longer time to relapse compared to those receiving placebo.

    14.2 Generalized Anxiety Disorder

    The efficacy of Petril Plus (Escitalopram) in the acute treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8 week, multicenter, flexible-dose, placebo-controlled studies that compared Petril Plus (Escitalopram) 10 to 20 mg/day to placebo in adult outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, Petril Plus (Escitalopram) showed statistically significant greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A).

    There were too few patients in differing ethnic and age groups to adequately assess whether or not Petril Plus (Escitalopram) has differential effects in these groups. There was no difference in response to Petril Plus (Escitalopram) between men and women.

    16 HOW SUPPLIED/STORAGE AND HANDLING

    Product: 63629-5349

    NDC: 63629-5349-1 30 TABLET, FILM COATED in a BOTTLE

    NDC: 63629-5349-2 60 TABLET, FILM COATED in a BOTTLE

    17 PATIENT COUNSELING INFORMATION

    See FDA-approved Medication Guide

    17.1 Information for Patients

    Physicians are advised to discuss the following issues with patients for whom they prescribe Petril Plus.

    General Information about Medication Guide

    Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Petril Plus (Escitalopram) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Petril Plus (Escitalopram). The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

    Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Petril Plus (Escitalopram).

    Clinical Worsening and Suicide Risk

    Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions (5.1)].

    Serotonin Syndrome

    Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Petril Plus (Escitalopram) with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2)].

    Abnormal Bleeding

    Patients should be cautioned about the concomitant use of Petril Plus (Escitalopram) and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions (5.7)].

    Angle Closure Glaucoma

    Patients should be advised that taking Petril Plus (Escitalopram) can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.9)].

    Concomitant Medications

    Since Petril Plus (Escitalopram) is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

    Continuing the Therapy Prescribed

    While patients may notice improvement with Petril Plus (Escitalopram) therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

    Interference with Psychomotor Performance

    Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Petril Plus (Escitalopram) therapy does not affect their ability to engage in such activities.

    Alcohol

    Patients should be told that, although Petril Plus (Escitalopram) has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of Petril Plus (Escitalopram) and alcohol in depressed patients is not advised.

    Pregnancy and Breastfeeding

    Patients should be advised to notify their physician if they

    • become pregnant or intend to become pregnant during therapy.
    • are breastfeeding an infant.

    Need for Comprehensive Treatment Program

    Petril Plus (Escitalopram) is indicated as an integral part of a total treatment program for MDD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all adolescents with this syndrome. Safety and effectiveness of Petril Plus (Escitalopram) in MDD has not been established in pediatric patients less than 12 years of age. Antidepressants are not intended for use in the adolescent who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe antidepressant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.

    Manufactured In India By:

    Cipla Ltd.

    Kurkumbh, India

    Manufactured For:

    Teva Pharmaceuticals USA, Inc.

    North Wales, PA 19454

    Rev. F 1/2017

    17.2 FDA-Approved Medication Guide

    MEDICATION GUIDE

    Petril Plus (Escitalopram) (ES-sye-TAL-oh-pram) Tablets USP

    Read the Medication Guide that comes with Petril Plus (Escitalopram) tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

    What is the most important information I should know about Petril Plus (Escitalopram) tablets?

    Petril Plus (Escitalopram) tablets and other antidepressant medicines may cause serious side effects, including:

    1. Suicidal thoughts or actions:

    • Petril Plus (Escitalopram) tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
    • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
    • Watch for these changes and call your healthcare provider right away if you notice:
      • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
      • Pay particular attention to such changes when Petril Plus (Escitalopram) tablets are started or when the dose is changed.

    Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

    Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

    • attempts to commit suicide
    • acting on dangerous impulses
    • acting aggressive or violent
    • thoughts about suicide or dying
    • new or worse depression
    • new or worse anxiety or panic attacks
    • feeling agitated, restless, angry or irritable
    • trouble sleeping
    • an increase in activity or talking more than what is normal for you
    • other unusual changes in behavior or mood


    Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Petril Plus (Escitalopram) tablets may be associated with these serious side effects:

    2. Serotonin Syndrome. This condition can be life-threatening and may include:

    • agitation, hallucinations, coma or other changes in mental status
    • coordination problems or muscle twitching (overactive reflexes)
    • racing heartbeat, high or low blood pressure
    • sweating or fever
    • nausea, vomiting, or diarrhea
    • muscle rigidity

    3. Severe allergic reactions:

    • trouble breathing
    • swelling of the face, tongue, eyes or mouth
    • rash, itchy welts (hives) or blisters, alone or with fever or joint pain

    4. Abnormal bleeding: Petril Plus (Escitalopram) tablets and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a nonsteroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

    5. Seizures or convulsions

    6. Manic episodes:

    • greatly increased energy
    • severe trouble sleeping
    • racing thoughts
    • reckless behavior
    • unusually grand ideas
    • excessive happiness or irritability
    • talking more or faster than usual

    7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

    8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

    • headache
    • weakness or feeling unsteady
    • confusion, problems concentrating or thinking or memory problems

    9. Visual problems

    • eye pain
    • changes in vision
    • swelling or redness in or around the eye
    • Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

    Do not stop Petril Plus (Escitalopram) tablets without first talking to your healthcare provider. Stopping Petril Plus (Escitalopram) tablets too quickly may cause serious symptoms including:

    • anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
    • headache, sweating, nausea, dizziness
    • electric shock-like sensations, shaking, confusion

    What are Petril Plus (Escitalopram) tablets?

    Petril Plus (Escitalopram) tablets are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Petril Plus (Escitalopram) tablets are also used to treat:

    • Major Depressive Disorder (MDD)
    • Generalized Anxiety Disorder (GAD)

    Talk to your healthcare provider if you do not think that your condition is getting better with Petril Plus (Escitalopram) tablets treatment.

    Who should not take Petril Plus (Escitalopram) tablets?

    Do not take Petril Plus (Escitalopram) tablets if you:

    • are allergic to Petril Plus (Escitalopram) oxalate or citalopram hydrobromide or any of the ingredients in Petril Plus (Escitalopram) tablets. See the end of this Medication Guide for a complete list of ingredients in Petril Plus (Escitalopram) tablets.
    • take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
      • Do not take an MAOI within 2 weeks of stopping Petril Plus (Escitalopram) tablets unless directed to do so by your physician.
      • Do not start Petril Plus (Escitalopram) tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
    • People who take Petril Plus (Escitalopram) tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:
      • high fever
      • uncontrolled muscle spasms
      • stiff muscles
      • rapid changes in heart rate or blood pressure
      • confusion
      • loss of consciousness (pass out)
    • take the antipsychotic medicine pimozide (Orap®) because taking this drug with Petril Plus (Escitalopram) tablets can cause serious heart problems.

    What should I tell my healthcare provider before taking Petril Plus (Escitalopram) tablets? Ask if you are not sure.

    Before starting Petril Plus (Escitalopram) tablets, tell your healthcare provider if you:

    • Are taking certain drugs such as:
      • Triptans used to treat migraine headache
      • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, amphetamines, or antipsychotics
      • Tramadol
      • Over-the-counter supplements such as tryptophan or St. John’s Wort
    • have liver problems
    • have kidney problems
    • have heart problems
    • have or had seizures or convulsions
    • have bipolar disorder or mania
    • have low sodium levels in your blood
    • have a history of a stroke
    • have high blood pressure
    • have or had bleeding problems
    • are pregnant or plan to become pregnant. It is not known if Petril Plus (Escitalopram) tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy
    • are breastfeeding or plan to breastfeed. Some Petril Plus (Escitalopram) may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Petril Plus (Escitalopram) tablets.

    Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Petril Plus (Escitalopram) tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.

    Your healthcare provider or pharmacist can tell you if it is safe to take Petril Plus (Escitalopram) tablets with your other medicines. Do not start or stop any medicine while taking Petril Plus (Escitalopram) tablets without talking to your healthcare provider first.


    If you take Petril Plus (Escitalopram) tablets, you should not take any other medicines that contain Petril Plus (Escitalopram) oxalate or citalopram hydrobromide including: Celexa.


    How should I take Petril Plus (Escitalopram) tablets?

    • Take Petril Plus (Escitalopram) tablets exactly as prescribed. Your healthcare provider may need to change the dose of Petril Plus (Escitalopram) tablets until it is the right dose for you.
    • Petril Plus (Escitalopram) tablets may be taken with or without food.
    • If you miss a dose of Petril Plus (Escitalopram) tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Petril Plus (Escitalopram) tablets at the same time.
    • If you take too many Petril Plus (Escitalopram) tablets, call your healthcare provider or poison control center right away, or get emergency treatment.

    What should I avoid while taking Petril Plus (Escitalopram) tablets?

    Petril Plus (Escitalopram) tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Petril Plus (Escitalopram) tablets affect you. Do not drink alcohol while using Petril Plus (Escitalopram) tablets.

    What are the possible side effects of Petril Plus (Escitalopram) tablets?

    Petril Plus (Escitalopram) tablets may cause serious side effects, including all of those described in the section entitled “What is the most important information I should know about Petril Plus (Escitalopram) tablets?

    Common possible side effects in people who take Petril Plus (Escitalopram) tablets include:

    • Nausea
    • Sleepiness
    • Weakness
    • Dizziness
    • Feeling anxious
    • Trouble sleeping
    • Sexual problems
    • Sweating
    • Shaking
    • Not feeling hungry
    • Dry mouth
    • Constipation
    • Infection
    • Yawning

    Other side effects in children and adolescents include:

    • increased thirst
    • abnormal increase in muscle movement or agitation
    • nose bleed
    • difficult urination
    • heavy menstrual periods
    • possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with Petril Plus (Escitalopram) tablets.

    Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Petril Plus (Escitalopram) tablets. For more information, ask your healthcare provider or pharmacist.

    CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.

    How should I store Petril Plus (Escitalopram) tablets?

    • Store Petril Plus (Escitalopram) tablets at 20° to 25°C (68° to 77°F).
    • Keep Petril Plus (Escitalopram) tablets bottle closed tightly.

    Keep Petril Plus (Escitalopram) tablets and all medicines out of the reach of children.

    General information about Petril Plus (Escitalopram) tablets

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Petril Plus (Escitalopram) tablets for a condition for which they were not prescribed. Do not give Petril Plus (Escitalopram) tablets to other people, even if they have the same condition. They may harm them.

    This Medication Guide summarizes the most important information about Petril Plus (Escitalopram) tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Petril Plus (Escitalopram) tablets that is written for healthcare professionals.

    For more information about Petril Plus (Escitalopram) tablets call Teva Pharmaceuticals at 1-888-838-2872.

    What are the ingredients in Petril Plus (Escitalopram) tablets?

    Active ingredient: Petril Plus (Escitalopram) oxalate

    Inactive ingredients: corn starch, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

    Manufactured In India By:

    Cipla Ltd.

    Kurkumbh, India

    Manufactured For:

    Teva Pharmaceuticals USA, Inc.

    North Wales, PA 19454

    Rev. E 1/2017

    Petril Plus 5mg Tablet

    Petril Plus pharmaceutical active ingredients containing related brand and generic drugs:

    infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


    Petril Plus available forms, composition, doses:

    infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
    Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
    Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


    Petril Plus destination | category:

    infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
    Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


    Petril Plus Anatomical Therapeutic Chemical codes:

    infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


    Petril Plus pharmaceutical companies:

    infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
    Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


    advertisement

    References

    1. Dailymed."ESCITALOPRAM TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
    2. Dailymed."CLONAZEPAM TABLET [MAJOR PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
    3. Dailymed."CLONAZEPAM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

    Frequently asked Questions

    Can i drive or operate heavy machine after consuming Petril Plus?

    Depending on the reaction of the Petril Plus after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Petril Plus not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

    Is Petril Plus addictive or habit forming?

    Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

    Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

    advertisement

    Review

    sDrugs.com conducted a study on Petril Plus, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Petril Plus consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

    Visitor reports

    One visitor reported side effects

    Did you get side effects while taking the Petril Plus drug, or were there no side effects?
    According to the survey conducted by website sDrugs.com users, the below-mentioned percentages indicate the number of people experiencing the side effects and the number of people not experiencing the side effects when taking Petril Plus medicine. Every drug produces minimal side effects, and they are negligible most times, when compared to the desired effect [use] of the medicine. Side effects depend on the dose you are taking, any drug interactions that happen when you are on other medications, if the patient is sensitive, and other associated conditions. If you cannot tolerate the side effects, consult your doctor immediately, so he can either adjust the dose or change the medication.
    Visitors%
    It has side effects1
    100.0%

    One visitor reported time for results

    What is the time duration Petril Plus drug must be taken for it to be effective or for it to reduce the symptoms?
    Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sDrugs.com website users needed 1 week to notice the result from using Petril Plus drug. The time needed to show improvement in health condition after using the medicine Petril Plus need not be same for all the users. It varies based on other factors.
    Visitors%
    1 week1
    100.0%

    One visitor reported administration

    The drugs are administered in various routes, like oral or injection form. They are administered before food or after food. How are you taking Petril Plus drug, before food or after food?
    Click here to find out how other users of our website are taking it. For any doubts or queries on how and when the medicine is administered, contact your health care provider immediately.
    Visitors%
    Empty stomach1
    100.0%

    Visitor reviews


    There are no reviews yet. Be the first to write one!


    Your name: 
    Email: 
    Spam protection:  < Type 20 here

    The information was verified by Dr. Arunabha Ray, MD Pharmacology

    © 2002 - 2019 "sDrugs.com". All Rights Reserved