Zapline

Zapline is indicated for the treatment of the following :

• Major depressive disorder (MDD)
• Obsessive-compulsive disorder (OCD)
• Panic disorder (PD)
• Posttraumatic stress disorder (PTSD)
• Social anxiety disorder (SAD)
• Premenstrual dysphoric disorder (PMDD)

Dosage In Patients With MDD, OCD, PD, PTSD, And SAD

The recommended initial dosage and maximum Zapline dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage.

For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of Zapline, the recommended interval between dose changes is one week.

Table 1: Recommended Daily Dosage of Zapline in Patients with MDD, OCD, PD, PTSD, and SAD

Dosage In Patients With PMDD

The recommended starting Zapline dosage in adult women with PMDD is 50 mg per day. Zapline may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle.

• When dosing continuously, patients not responding to a 50 mg dosage may benefit from dosage increases at 50 mg increments per menstrual cycle up to 150 mg per day.
• When dosing intermittently, patients not responding to a 50 mg dosage may benefit from increasing the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle.

Screen For Bipolar Disorder Prior To Starting Zapline

Prior to initiating treatment with Zapline or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania.

Dosage Modifications In Patients With Hepatic Impairment

Both the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage. The use of Zapline in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10- 15) is not recommended.

Switching Patients To Or From A Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of Zapline. In addition, at least 14 days must elapse after stopping Zapline before starting an MAOI antidepressant.

Discontinuation Of Treatment With Zapline

Adverse reactions may occur upon discontinuation of Zapline. Gradually reduce the dosage rather than stopping Zapline abruptly whenever possible.

Preparation Of Zapline Oral Solution

Zapline oral solution must be diluted before use.

• Use the supplied calibrated dropper to measure the amount of Zapline oral solution needed
• Note: The supplied calibrated dropper has 25 mg and 50 mg graduation marks only
• Mix with 4 ounces (½ cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. After mixing, a slight haze may appear, which is normal.

Instruct patients or caregivers to immediately take the dose after mixing.

Zapline is contraindicated in patients:

• Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.
• Taking pimozide.
• With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema).

In addition to the contraindications for all Zapline formulations listed above, Zapline oral solution is contraindicated in patients:

• Taking disulfiram. Zapline oral solution contains contain alcohol, and concomitant use of Zapline and disulfiram may result in a disulfiram-alcohol reaction.

Store Zapline tablets and oral solution at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Distributed by: Roerig, Division of Pfizer Inc., NY,NY 10017. Revised: Dec 2017

SIDE EFFECTS

The following adverse reactions are described in more detail in other sections of the prescribing information:

• Hypersensitivity reactions to sertraline
• Disulfiram-alcohol reaction when Zapline oral solution is taken with disulfiram
• QTc prolongation and ventricular arrhythmias when taken with pimozide
• Suicidal thoughts and behaviors
• Serotonin syndrome
• Increased risk of bleeding
• Activation of mania/hypomania
• Discontinuation syndrome
• Seizures
• Angle-closure glaucoma
• Hyponatremia

Clinical Trials Experience

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

The data described below are from randomized, double-blind, placebo-controlled trials of Zapline (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to Zapline for 8 to12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males.

The most common adverse reactions (>5% and twice placebo) in all pooled placebo-controlled clinical trials of all Zapline-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of Zapline (>5% and twice placebo) by indication that were not mentioned previously.

• MDD: somnolence;
• OCD: insomnia, agitation;
• PD: constipation, agitation;
• PTSD: fatigue;
• PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain;
• SAD: insomnia, dizziness, fatigue, dry mouth, malaise.

Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD*

Adverse Reactions Leading To Discontinuation In Placebo-Controlled Clinical Trials

In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received Zapline discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in Zapline-treated patients:

• MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%).
• MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.
• OCD: somnolence.
• PD: nervousness and somnolence.

Male And Female Sexual Dysfunction

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 SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of Zapline-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido.

Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from Zapline Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD

Adverse Reactions In Pediatric Patients

In 281 pediatric patients treated with Zapline in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety.

Other Adverse Reactions Observed During The Premarketing Evaluation Of Zapline

Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with Zapline were:

Cardiac disorders – tachycardia

Ear and labyrinth disorders – tinnitus

Endocrine disorders - hypothyroidism

Eye disorders - mydriasis, blurred vision

Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage

General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia

Hepatobiliary disorders - elevated liver enzymes

Immune system disorders - anaphylaxis

Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite

Musculoskeletal and connective tissue disorders - arthralgia, muscle spasms, tightness, or twitching

Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope

Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination

Renal and urinary disorders - hematuria

Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage

Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning

Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura;erythematous, follicular, or maculopapular rash; urticaria

Vascular disorders – hemorrhage, hypertension, vasodilation

Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Zapline. Because these reactions are 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.

Bleeding or clotting disorders - increased coagulation times (altered platelet function)

Cardiac disorders - AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes)

Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH

Eye disorders - blindness, optic neuritis, cataract

Hepatobiliary disorders - severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis

Hemic and lymphatic disorders - agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness

Immune system disorders - angioedema

Metabolism and nutrition disorders - hyponatremia, hyperglycemia

Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus

Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis

Psychiatric disorders - psychosis, enuresis, paroniria

Renal and urinary disorders - acute renal failure

Respiratory, thoracic and mediastinal disorders - pulmonary hypertension

Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)

Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis

DRUG INTERACTIONS

Clinically Significant Drug Interactions

Table 5 includes clinically significant drug interactions with Zapline.

Table 5: Clinically-Significant Drug Interactions with Zapline

Drugs Having No Clinically Important Interactions With Zapline

Based on pharmacokinetic studies, no dosage adjustment of Zapline is necessary when used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam, lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when Zapline is administered concomitantly.

False-Positive Screening Tests For Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Zapline. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Zapline. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

Drug Abuse And Dependence

Controlled Substance

Zapline contains sertraline, which is not a controlled substance.

Abuse

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of Zapline, alprazolam, and d-amphetamine in humans, Zapline did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Suicidal Thoughts And Behaviors In Pediatric And Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

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

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Zapline, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Zapline, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased 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, i.e., MAOIs. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Zapline with MAOIs is contraindicated. In addition, do not initiate Zapline in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Zapline, discontinue Zapline before initiating treatment with the MAOI.

Monitor all patients taking Zapline for the emergence of serotonin syndrome. Discontinue treatment with Zapline and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Zapline with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Increased Risk Of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including Zapline, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients of the increased risk of bleeding associated with the concomitant use of Zapline and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

Activation Of Mania Or Hypomania

Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.

Seizures

Zapline has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Zapline should be prescribed with caution in patients with a seizure disorder.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Zapline may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Zapline, in patients with untreated anatomically narrow angles.

Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Zapline. Cases with serum sodium lower than 110 mmol/L have been reported. 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 or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue Zapline and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

False-Positive Effects On Screening Tests For Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Zapline. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Zapline. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Zapline from benzodiazepines.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts And Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider.

Important Administration Instructions for Oral Solution

For patients prescribed Zapline oral solution, inform them that:

• Zapline oral solution must be diluted before use. Do not mix in advance.
• Use the dropper provided to remove the required amount of Zapline oral solution and mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix Zapline oral solution with anything other than the liquids listed.
• Take the dose immediately after mixing. At times, a slight haze may appear after mixing; this is normal.
• The dropper dispenser contains dry natural rubber, a consideration for patients with latex sensitivity.

Disulfiram Contraindication For Zapline Oral Solution

Inform patients not to take disulfiram when taking Zapline oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of Zapline with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Increased Risk Of Bleeding

Inform patients about the concomitant use of Zapline with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-thecounter medications that increase the risk of bleeding.

Activation Of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider.

Discontinuation Syndrome

Advise patients not to abruptly discontinue Zapline and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Zapline is discontinued.

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.

Pregnancy

Inform pregnant women that Zapline may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment O