The most common signs and symptoms associated with non-fatal Irradial overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. No cases of fatal overdosage with only sertraline have been reported.
Other important adverse events reported with Irradial overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QTc-interval prolongation, Torsade de Pointes, serotonin syndrome, stupor, and syncope.
Overdose ManagementNo specific antidotes for Irradial are known. Contact Poison Control (1-800-222-1222) for latest recommendations.
Irradial is contraindicated in patients:
In addition to the contraindications for all Irradial formulations listed above, Irradial oral solution is contraindicated in patients:
Store Irradial 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 & Drug Interactions SIDE EFFECTSThe following adverse reactions are described in more detail in other sections of the prescribing information:
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 Irradial (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 Irradial 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 Irradial-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 Irradial (>5% and twice placebo) by indication that were not mentioned previously.
Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD*
| Irradial (N=3066) | Placebo (N=2293) | |
| Cardiac disorders | ||
| Palpitations | 4% | 2% |
| Eye disorders | ||
| Visual impairment | 4% | 2% |
| Gastrointestinal Disorders | ||
| Nausea | 26% | 12% |
| Diarrhea/Loose Stools | 20% | 10% |
| Dry mouth | 14% | 9% |
| Dyspepsia | 8% | 4% |
| Constipation | 6% | 4% |
| Vomiting | 4% | 1% |
| General disorders and administration site conditions | ||
| Fatigue | 12% | 8% |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 7% | 2% |
| Nervous system disorders | ||
| Dizziness | 12% | 8% |
| Somnolence | 11% | 6% |
| Tremor | 9% | 2% |
| Psychiatric Disorders | ||
| Insomnia | 20% | 13% |
| Agitation | 8% | 5% |
| Libido Decreased | 6% | 2% |
| Reproductive system and breast disorders | ||
| Ejaculation failure (1) | 8% | 1% |
| Erectile dysfunction (1) | 4% | 1% |
| Ejaculation disorder (1) | 3% | 0% |
| Male sexual dysfunction (1) | 2% | 0% |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 7% | 3% |
| 1 Denominator used was for male patients only (n=1316 Irradial; n=973 placebo). * Adverse reactions that occurred greater than 2% in Irradial-treated patients and at least 2% greater in Irradial-treated patients than placebo-treated patients. | ||
In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received Irradial 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 Irradial-treated patients:
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 Irradial-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 Irradial Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD
| Men only | Irradial (N=1316) | Placebo (N=973) |
| Ejaculation failure | 8% | 1% |
| Libido decreased | 7% | 2% |
| Erectile dysfunction | 4% | 1% |
| Ejaculation disorder | 3% | 0% |
| Male sexual dysfunction | 2% | 0% |
| Women only | (N=1750) | (N=1320) |
| Libido decreased | 4% | 2% |
In 281 pediatric patients treated with Irradial 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 IrradialOther infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with Irradial 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 ExperienceThe following adverse reactions have been identified during postapproval use of Irradial. 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 InteractionsTable 5 includes clinically significant drug interactions with Irradial.
Table 5: Clinically-Significant Drug Interactions with Irradial
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | The concomitant use of SSRIs including Irradial and MAOIs increases the risk of serotonin syndrome. |
| Intervention: | Irradial is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue. |
| Examples: | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
| Pimozide | |
| Clinical Impact: | Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. |
| Intervention: | Concomitant use of pimozide and Irradial is contraindicated. |
| Other Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of serotonergic drugs with Irradial increases the risk of serotonin syndrome. |
| Intervention: | Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Irradial and/or concomitant serotonergic drugs. |
| Examples: | other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
| Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) | |
| Clinical Impact: | The concurrent use of an antiplatelet agent or anticoagulant with Irradial may potentiate the risk of bleeding. |
| Intervention: | Inform patients of the increased risk of bleeding associated with the concomitant use of Irradial and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. |
| Examples: | aspirin, clopidogrel, heparin, warfarin |
| Drugs Highly Bound to Plasma Protein | |
| Clinical Impact: | Irradial is highly bound to plasma protein. The concomitant use of Irradial with another drug that is highly bound to plasma protein may increase free concentrations of Irradial or other tightly-bound drugs in plasma. |
| Intervention: | Monitor for adverse reactions and reduce dosage of Irradial or other protein-bound drugs as warranted. |
| Examples: | warfarin |
| Drugs Metabolized by CYP2D6 | |
| Clinical Impact: | Irradial is a CYP2D6 inhibitor. The concomitant use of Irradial with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. |
| Intervention: | Decrease the dosage of a CYP2D6 substrate if needed with concomitant Irradial use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if Irradial is discontinued. |
| Examples: | propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
| Phenytoin | |
| Clinical Impact: | Phenytoin is a narrow therapeutic index drug. Irradial may increase phenytoin concentrations. |
| Intervention: | Monitor phenytoin levels when initiating or titrating Irradial. Reduce phenytoin dosage if needed. |
| Examples: | phenytoin, fosphenytoin |
| Drugs that Prolong the QTc Interval | |
| Clinical Impact: | The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval. |
| Intervention: | Pimozide is contraindicated for use with sertraline. Avoid the concomitant use of drugs known to prolong the QTc interval. |
| Examples: | Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). |
Based on pharmacokinetic studies, no dosage adjustment of Irradial 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 Irradial is administered concomitantly.
False-Positive Screening Tests For BenzodiazepinesFalse-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Irradial. 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 Irradial. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.
Drug Abuse And Dependence Controlled SubstanceIrradial contains sertraline, which is not a controlled substance.
AbuseIn a placebo-controlled, double-blind, randomized study of the comparative abuse liability of Irradial, alprazolam, and d-amphetamine in humans, Irradial 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 & Precautions WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS Suicidal Thoughts And Behaviors In Pediatric And Young Adult PatientsIn 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
| Age Range (years) | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
| Increases Compared to Placebo | |
| <18 | 14 additional patients |
| 18-24 | 5 additional patients |
| Decreases Compared to Placebo | |
| 25-64 | 1 fewer patient |
| ≥65 | 6 fewer 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 Irradial, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Serotonin SyndromeSerotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Irradial, 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 Irradial with MAOIs is contraindicated. In addition, do not initiate Irradial 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 Irradial, discontinue Irradial before initiating treatment with the MAOI.
Monitor all patients taking Irradial for the emergence of serotonin syndrome. Discontinue treatment with Irradial and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Irradial with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
Increased Risk Of BleedingDrugs that interfere with serotonin reuptake inhibition, including Irradial, 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 Irradial and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
Activation Of Mania Or HypomaniaIn patients with bipolar disorder, treating a depressive episode with Irradial or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with Irradial. Prior to initiating treatment with Irradial, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
Discontinuation SyndromeAdverse 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.
SeizuresIrradial has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Irradial should be prescribed with caution in patients with a seizure disorder.
Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including Irradial 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 Irradial, in patients with untreated anatomically narrow angles.
HyponatremiaHyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Irradial. 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 Irradial 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 BenzodiazepinesFalse-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Irradial. 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 Irradial. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Irradial from benzodiazepines.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts And BehaviorsAdvise 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 SolutionFor patients prescribed Irradial oral solution, inform them that:
Inform patients not to take disulfiram when taking Irradial oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution.
Serotonin SyndromeCaution patients about the risk of serotonin syndrome, particularly with the concomitant use of Irradial 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 BleedingInform patients about the concomitant use of Irradial 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/HypomaniaAdvise 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 SyndromeAdvise patients not to abruptly discontinue Irradial and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Irradial is discontinued.
Allergic ReactionsAdvise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
PregnancyInform pregnant women that Irradial may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment OThe following adverse reactions are described in more detail in other sections of the prescribing information:
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 Irradial (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 Irradial 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 Irradial-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 Irradial (>5% and twice placebo) by indication that were not mentioned previously.
Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD*
| Irradial (N=3066) | Placebo (N=2293) | |
| Cardiac disorders | ||
| Palpitations | 4% | 2% |
| Eye disorders | ||
| Visual impairment | 4% | 2% |
| Gastrointestinal Disorders | ||
| Nausea | 26% | 12% |
| Diarrhea/Loose Stools | 20% | 10% |
| Dry mouth | 14% | 9% |
| Dyspepsia | 8% | 4% |
| Constipation | 6% | 4% |
| Vomiting | 4% | 1% |
| General disorders and administration site conditions | ||
| Fatigue | 12% | 8% |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 7% | 2% |
| Nervous system disorders | ||
| Dizziness | 12% | 8% |
| Somnolence | 11% | 6% |
| Tremor | 9% | 2% |
| Psychiatric Disorders | ||
| Insomnia | 20% | 13% |
| Agitation | 8% | 5% |
| Libido Decreased | 6% | 2% |
| Reproductive system and breast disorders | ||
| Ejaculation failure (1) | 8% | 1% |
| Erectile dysfunction (1) | 4% | 1% |
| Ejaculation disorder (1) | 3% | 0% |
| Male sexual dysfunction (1) | 2% | 0% |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 7% | 3% |
| 1 Denominator used was for male patients only (n=1316 Irradial; n=973 placebo). * Adverse reactions that occurred greater than 2% in Irradial-treated patients and at least 2% greater in Irradial-treated patients than placebo-treated patients. | ||
In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received Irradial 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 Irradial-treated patients:
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 Irradial-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 Irradial Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD
| Men only | Irradial (N=1316) | Placebo (N=973) |
| Ejaculation failure | 8% | 1% |
| Libido decreased | 7% | 2% |
| Erectile dysfunction | 4% | 1% |
| Ejaculation disorder | 3% | 0% |
| Male sexual dysfunction | 2% | 0% |
| Women only | (N=1750) | (N=1320) |
| Libido decreased | 4% | 2% |
In 281 pediatric patients treated with Irradial 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 IrradialOther infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with Irradial 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 ExperienceThe following adverse reactions have been identified during postapproval use of Irradial. 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
Irradial is indicated for the treatment of the following :
Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase.
AlcoholIn healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by Irradial.
Cardiac ElectrophysiologyThe effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N- desmethylsertraline concentrations. These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis.
Following oral once-daily Irradial dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. The single dose bioavailability of Irradial tablets is approximately equal to an equivalent dose of Irradial oral solution. Administration with food causes a small increase in Cmax and AUC.
MetabolismSertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24-hour), Cmax and Cmin, with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.
Protein BindingIn vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Suicidal Thoughts And Behaviors In Pediatric And Young Adult PatientsIn 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
| Age Range (years) | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
| Increases Compared to Placebo | |
| <18 | 14 additional patients |
| 18-24 | 5 additional patients |
| Decreases Compared to Placebo | |
| 25-64 | 1 fewer patient |
| ≥65 | 6 fewer 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 Irradial, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Serotonin SyndromeSerotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Irradial, 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 Irradial with MAOIs is contraindicated. In addition, do not initiate Irradial 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 Irradial, discontinue Irradial before initiating treatment with the MAOI.
Monitor all patients taking Irradial for the emergence of serotonin syndrome. Discontinue treatment with Irradial and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Irradial with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
Increased Risk Of BleedingDrugs that interfere with serotonin reuptake inhibition, including Irradial, 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 Irradial and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
Activation Of Mania Or HypomaniaIn patients with bipolar disorder, treating a depressive episode with Irradial or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with Irradial. Prior to initiating treatment with Irradial, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
Discontinuation SyndromeAdverse 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.
SeizuresIrradial has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Irradial should be prescribed with caution in patients with a seizure disorder.
Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including Irradial 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 Irradial, in patients with untreated anatomically narrow angles.
HyponatremiaHyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Irradial. 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 Irradial 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 BenzodiazepinesFalse-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Irradial. 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 Irradial. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Irradial from benzodiazepines.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts And BehaviorsAdvise 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 SolutionFor patients prescribed Irradial oral solution, inform them that:
Inform patients not to take disulfiram when taking Irradial oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution.
Serotonin SyndromeCaution patients about the risk of serotonin syndrome, particularly with the concomitant use of Irradial 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 BleedingInform patients about the concomitant use of Irradial 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/HypomaniaAdvise 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 SyndromeAdvise patients not to abruptly discontinue Irradial and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Irradial is discontinued.
Allergic ReactionsAdvise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
PregnancyInform pregnant women that Irradial may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisLifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect was not clearly drug related.
MutagenesisSertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment Of FertilityA decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m2 basis in adolescents).
Use In Specific Populations Pregnancy Risk SummaryOverall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive [See Data]. There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including Irradial, during the third trimester of pregnancy [See Clinical Considerations].
Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m2 basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD [See Data].
The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing Irradial.
Irradial oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.
Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk
A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Fetal/Neonatal adverse reactions
Exposure to SSRIs and SNRIs, including Irradial in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).
When treating a pregnant woman with Irradial during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to Irradial in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data].
Data Human DataThird Trimester Exposure
Neonates exposed to Irradial and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. 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. In some cases, the clinical picture was consistent with serotonin syndrome.
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”.
First Trimester Exposure
The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70-1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations.
Animal DataReproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg 0.8 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.
Lactation Risk SummaryAvailable data from published literature demonstrate low levels of sertraline and its metabolites in human milk [See Data]. There are no data on the effects of sertraline on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Irradial and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.
DataIn a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants.
Pediatric UseThe safety and efficacy of Irradial have been established in the treatment of OCD in pediatric patients aged 6 to 17. Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients.
Monitoring Pediatric Patients Treated With IrradialMonitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases. Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as Irradial.
Weight Loss In Studies In Pediatric Patients With MDDIn a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between Irradial and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the Irradial group compared to a slight gain for the placebo group. For children, about 7% of the Irradial-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of Irradial-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.
A subset of patients who completed the randomized controlled trials in patients with MDD (Irradial n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of Irradial treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of Irradial on the growth, development, and maturation in pediatric patients.
Alcohol Content In Irradial Oral SolutionIrradial oral solution contains 12% alcohol.
Juvenile Animal DataA study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.
In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 -17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).
Geriatric UseOf the total number of patients in clinical studies of Irradial in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old.
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. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In 354 geriatric subjects treated with Irradial in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3, except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.
SNRIs and SSRIs, including Irradial, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.
Hepatic ImpairmentThe recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. The use of Irradial in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10-15) is not recommended, because Irradial is extensively metabolized, and the effects of Irradial in patients with moderate and severe hepatic impairment have not been studied.
Renal ImpairmentNo dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does not appear to be affected by renal impairment.
The recommended initial dosage and maximum Irradial 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 Irradial, the recommended interval between dose changes is one week.
Table 1: Recommended Daily Dosage of Irradial in Patients with MDD, OCD, PD, PTSD, and SAD
| Indication | Starting Dose | Therapeutic Range |
| Adults | ||
| MDD | 50 mg | 50-200 mg |
| OCD | 50 mg | |
| PD, PTSD, SAD | 25 mg | |
| Pediatric Patients | ||
| OCD (ages 6-12 years old) | 25 mg | 50-200 mg |
| OCD (ages 13-17 years old) | 50 mg | |
The recommended starting Irradial dosage in adult women with PMDD is 50 mg per day. Irradial 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.
Prior to initiating treatment with Irradial or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania.
Dosage Modifications In Patients With Hepatic ImpairmentBoth 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 Irradial 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 AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of Irradial. In addition, at least 14 days must elapse after stopping Irradial before starting an MAOI antidepressant.
Discontinuation Of Treatment With IrradialAdverse reactions may occur upon discontinuation of Irradial. Gradually reduce the dosage rather than stopping Irradial abruptly whenever possible.
Preparation Of Irradial Oral SolutionIrradial oral solution must be diluted before use.
Instruct patients or caregivers to immediately take the dose after mixing.
