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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
PAXIL (NDA-020710)
(PAROXETINE HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
09/23/2026 (SUPPL-49)
4 Contraindications
Additions and/or revisions underlined:
PAXIL 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 [see Warnings and Precautions (5.2) and Drug Interactions (7)].
- Who receive drugs that can prolong QTc interval and are also CYP450 2D6 substrates [see Drug Interactions (7) and Warnings and Precautions (5.3)]
- With known hypersensitivity to paroxetine or any of the inactive ingredients in PAXIL. Hypersensitivity reactions have included anaphylaxis, angioedema, and Stevens-Johnson syndrome [see Adverse Reactions (6.1), (6.2)].
5 Warnings and Precautions
5.1 Suicidal Thoughts and Behaviors in Pediatric Patients and Young Adults
Subsection title revised.
Additions and/or revisions underlined
. . .
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric patients and young adults 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 and that depression itself is a risk factor for suicidal thoughts and behaviors.
Closely 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 PAXIL, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
5.2 Serotonin Syndrome
Additions and/or revisions underlined:
. . .
Selective serotonin reuptake inhibitors (SSRIs), including PAXIL, 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, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when PAXIL is used alone.
. . .
The concomitant use of PAXIL with MAOIs is contraindicated. In addition, do not initiate PAXIL 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 of administration (such as orally or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PAXIL discontinue PAXIL before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7)].
. . .
5.3 Drug Interactions Leading to QTc Interval Prolongation
Additions and/or revisions underlined:
Cases of QTc interval prolongation have been reported with the use of paroxetine, although causal relationship with PAXIL has not been established.
PAXIL is a strong CYP2D6 inhibitor. Concomitant use of PAXIL with CYP2D6 substrates that prolong the QTc interval can increase the concentration of those CYP2D6 substrates and may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death.
The concomitant use of PAXIL is contraindicated with CYP2D6 substrates that prolong the QTc interval [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
5.4 Embryofetal Toxicity
Additions and/or revisions underlined:
PAXIL can cause fetal harm when administered to a pregnant woman. Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants.
. . .
5.5 Increased Risk of Bleeding
Additions and/or revisions underlined:
. . .
Inform patients about the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio when initiating, titrating, or discontinuing PAXIL.
5.6 Activation of Mania or Hypomania
Additions and/or revisions underlined:
In patients with bipolar disorder, treating a depressive episode with PAXIL or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of PAXIL for unipolar depression, hypomania or mania occurred in approximately 1% of PAXIL-treated patients compared to 1.1% of active-control and 0.3% of placebo-treated patients.
. . .
5.7 Discontinuation Syndrome
Additions and/or revisions underlined:
. . .
During clinical trials of GAD and PTSD, gradual decreases in the daily PAXIL dosage by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for PAXIL and were at least twice that reported for placebo: abnormal dreams, paresthesia, and dizziness adverse reactions have been reported upon discontinuation of treatment with PAXIL in pediatric patients. The safety and effectiveness of PAXIL in pediatric patients have not been established [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].
When discontinuing PAXIL, a gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)].
5.10 Hyponatremia
Additions and/or revisions underlined:
Hyponatremia may occur as a result of treatment with SSRIs, including PAXIL. 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 and/or acute hyponatremia 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).
. . .
5.11 Sexual Dysfunction
Additions and/or revisions underlined:
. . .
Recommend prescribers inquire about sexual function prior to initiation of PAXIL and to inquire specifically about changes in sexual function during PAXIL treatment because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtain a detailed history (including timing of symptom onset) because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment for sexual dysfunction.
5.12 Risk of Reduced of Efficacy of Tamoxifen
Subsection title revised.
Additions and/or revisions underlined:
Some studies have shown that the efficacy of tamoxifen, as measured by breast cancer relapse and mortality, may be reduced with concomitant use of PAXIL as a result of paroxetine’s irreversible CYP2D6 inhibition and lower concentration of the active metabolite of tamoxifen [see Drug Interactions (7)]. One study suggested that the risk may increase with longer duration of concomitant use of PAXIL and tamoxifen. However, other studies have failed to demonstrate such a risk.
When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition rather than PAXIL.
5.13 Fracture Risk
Subsection title revised.
Additions and/or revisions underlined:
Epidemiological studies on fracture risk during exposure to some antidepressant drugs, including SSRIs, have reported an association between antidepressant drug treatment and fractures. There are multiple possible causes for this association, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.
6 Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information.
6.2 Postmarketing Experience
Extensive changes; please refer to label for complete information7 Drug Interactions
Extensive changes to Table 9: Clinically Significant Drug Interactions with PAXIL; please refer to label for complete information.
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
. . .
Risk Summary
. . .
Also, consider the risks of untreated depression when discontinuing or changing treatment with antidepressant drugs during pregnancy and the postpartum period pregnancy (see Clinical Considerations).
No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses in rats are approximately 8 times the maximum recommended human dose (MRHD – 60 mg) and in rabbits less than 2 MRHD) on an mg/m2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis (see Data).
The estimated background risks of major birth defects and miscarriage in pregnant adults with MDD, OCD, PD, SAD, GAD, or PTSD are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/fetal Risk: Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of MDD who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressants during pregnancy and the postpartum period.
. . .
Fetal/Neonatal Adverse Reactions: Neonates of mothers exposed to PAXIL and other SSRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions (5.4)].
Data
. . .
Animal Data: Reproduction studies were performed at paroxetine doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 times (rat) and less than 2 times (rabbit) the maximum recommended human dose (MRHD – 60 mg) of PAXIL on an mg/m2 basis. These studies revealed no evidence of developmental effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
8.2 Lactation
Additions and/or revisions underlined:
. . .
Clinical Considerations
Infants exposed to PAXIL through breastfeeding should be monitored for agitation, irritability, poor feeding and poor weight gain.
Data
Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk/plasma ratio of <1. No significant amounts of paroxetine were detected in the plasma of infants after breastfeeding.
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of PAXIL in pediatric patients have not been established. Safety and effectiveness of PAXIL for the treatment of MDD in pediatric patients was not demonstrated in three placebo-controlled trials in 752 PAXIL-treated pediatric patients with MDD.
Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs in pediatric patients.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of PAXIL-treated pediatric patients and occurred at a rate at least twice that for placebo-treated pediatric patients: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
Adverse reactions upon discontinuation of treatment with PAXIL (occurred in at least 2% of PAXIL-treated patients and at a rate at least twice that of placebo-treated patients) in the pediatric clinical trials that included a taper phase regimen were emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.
8.5 Geriatric Use
Additions and/or revisions underlined:
SSRIs including PAXIL, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)].
In premarketing clinical trials with PAXIL, 17% of PAXIL-treated patients (approximately 700) were 65 years of age or older. Clinical studies of PAXIL did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. The minimum plasma concentration (Cmin) of paroxetine was higher in PAXIL-treated patients 65 years of age and older compared to younger adult patients [see Clinical Pharmacology (12.3)]; therefore, the starting recommended dosage is lower in patients 65 years of age and older with MDD, OCD, PTSD, and SAD and the maximum recommended dosage of PAXIL is lower in patients 65 years of age and older with MDD, OCD, PD, PTSD, SAD, and GAD [see Dosage and Administration (2)].
8.6 Renal Impairment
Compared to those without renal impairment (RI), paroxetine plasma concentrations in patients with RI, which may increase the risk of paroxetine-associated adverse reactions. Paroxetine plasma concentrations were higher in patients with greater degrees of RI.
The recommended starting and maximum dosage of PAXIL is lower in patients with severe RI compared to those without RI [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. The recommended PAXIL dosage in patients with mild RI or moderate RI is the same as in those without RI.
8.7 Hepatic Impairment
Additions and/or revisions underlined:
Compared to those without hepatic impairment (HI), paroxetine plasma concentrations in patients with severe hepatic impairment (HI) were increased, which may increase the risk of paroxetine-associated adverse reactions.
The recommended starting and maximum dosage of PAXIL is lower in patients with severe HI compared to those without HI [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. The recommended dosage in patients with mild or moderate HI is the same as in those without HI.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Medication Guide has undergone extensive change; please refer to label for complete information.
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Suicidal Thoughts and Behaviors
Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during PAXIL treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.1)].
. . .
Potential for Drug Interactions with Concomitant Drugs
Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or nonprescription drugs, since there is a potential for drug-drug interactions [see Warning and Precautions (5.3, 5.12) and Drug Interactions (7)].
. . .
Embryo-Fetal Toxicity
Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PAXIL. Advise women of the risks of PAXIL associated with [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]:
- First trimester use.
- Third trimester use including an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).
Advise women of the risks associated with untreated depression in pregnancy in those being treated for MDD.
Advise women of the availability of a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PAXIL during pregnancy.
. . .
Hypersensitivity Reactions
Advise patients to notify their healthcare provider if they develop a hypersensitivity reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.1, 6.2)].
. . .
08/18/2023 (SUPPL-50)
5 Warnings and Precautions
5.2 Serotonin SyndromeAdditions and revisions underlined:
SSRIs, including PAXIL, 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, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)].
Newly added information:
Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)].
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and revisions underlined:
The following reactions have been identified during post approval use of PAXIL. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women.
7 Drug Interactions
Addition of opioids and amphetamines to table
8 Use in Specific Populations
8.1 PregnancyNewly added information:
Risk Summary
Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations].
. . .
Maternal Adverse Reactions
Use of PAXIL in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
Especially tell your healthcare provider if you take:
tramadol, fentanyl, meperidine, methadone, or other opioids
Additions and revisions underlined:
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PAXIL with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, 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).
09/20/2021 (SUPPL-47)
5 Warnings and Precautions
5.13 Sexual Dysfunction(Newly added subsection)
Use of SSRIs, including PAXIL, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of PAXIL and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Sexual Dysfunction [see Warnings and Precautions (5.13)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
…
Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PAXIL, may cause sexual problems.
Symptoms in males may include:
Delayed ejaculation or inability to have an ejaculation
Decreased sex drive
- Problems getting or keeping an erection
Symptoms in females may include:
Decreased sex drive
Delayed orgasm or inability to have an orgasm
Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PAXIL. There may be treatments your healthcare provider can suggest.
…
(Additions and/or revisions underlined)
…
Sexual Dysfunction
Advise patients that use of PAXIL may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13)].
…
02/06/2021 (SUPPL-45)
Boxed Warning
(Extensive changes; please refer to label)
Other
(PLR conversion. Please refer to label for complete information.)
01/04/2017 (SUPPL-38)
5 Warnings and Precautions
Serotonin SyndromeAdditions and/or revisions underlined:
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PAXIL 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) …
If concomitant use of PAXIL with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines and St. John’s Wort is clinically warranted …
7 Drug Interactions
Additions and/or revisions underlined:
Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort.