Bella®

Bupropion HCl

Bupropion exhibits a greater potential for causing seizures than other antidepressants; the incidence of seizures with bupropion exceeds that of other commercially available antidepressants by up to 4-fold.144 The incidence of seizures occurring with bupropion is dose-dependent. Seizures occur in roughly 0.1% of patients receiving up to 300 mg/day (sustained-release) and 0.4% of patients receiving up to 450 mg/day (immediate-release) of bupropion. According to the manufacturer, the incidence of seizures in patients taking Wellbutrin XL as a single dose of 450 mg is 0.4%. Although seizure incidence has not been evaluated in clinical trials of the extended-release formulation of bupropion, its bioequivalence with the immediate-release and sustained-release formulations suggests that the risk may be similar to that encountered with use of these products. The incidence of seizures rises disproportionately at dosages > 450 mg/day (immediate-release).1 In patients receiving a 600-mg/day immediate-release regimen of bupropion, the risk of seizures was estimated to be 10-fold that of patients administered the 450-mg maximum daily recommended dose. The incidence of seizures during use of bupropion hydrobromide (Aplenzin) has not been formally evaluated by the manufacturer. To limit the risk of seizures, recommended single or maximum daily dosages of any dosage form of bupropion should not be exceeded. Some patients may be more at risk of experiencing seizures with bupropion therapy. The use or withdrawal of some medication regimens, including ethanol, may lower seizure threshold; these should be utilized cautiously with bupropion. When possible, concomitant use of these medications with bupropion should be avoided.4243444546

During clinical trials of immediate-release or extended-release bupropion formulations, the following centrally-mediated effects occurred more frequently with bupropion that placebo: insomnia (11—31% vs 6—21%), dizziness (6—11% vs 5—7%), tremor (2—21.1% vs < 1—7.6%), drowsiness (2—3% vs 1—2%), sedation or lethargy (19.8% vs 19.5%), cutaneous temperature disturbance (1.9% vs 1.6%), headache (25—34% vs 22.2—26%), migraine (1—25.7% vs 1—22.2%), impaired sleep quality (4% vs 1.6%), paresthesias (1—2% vs 1%), CNS stimulation or restlessness (1—2% vs 1%), and feeling jittery (3% vs 2%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following CNS effects and incidences were reported: insomnia (40%, 28%, 45%, 18%) and nervousness (1%, < 1%, 2%, 0%). The incidence of ataxia/incoordination ranged from < 0.1% to >= 1% of patients during pre-marketing or post-marketing use of bupropion. CNS effects reported in 0.1—1% of patients included vertigo, dysarthria, abnormal coordination, CNS stimulation, hypesthesia, and paresthesias. Rarely reported effects (< 0.1%) included EEG changes, abnormal neurological exam, impaired attention, and aphasia. Also observed were coma, neuralgia (neuropathic pain), neuropathy, and restlessness. Some symptoms may be dose-related and may respond to dosage reduction. To limit insomnia, do not give doses close to bedtime. In some cases these symptoms may require treatment with sedative/hypnotic therapy. In roughly 2% of patients treated, CNS symptoms will necessitate drug discontinuation.4243444546

All effective antidepressants can precipitate mania in predisposed individuals suffering from bipolar disorder. Mania and hypomania have been reported in 1% or more of bupropion recipients during clinical trials. Hypomania was reported rarely (less than 0.1%) during other pre-marketing evaluations. If mania occurs, bupropion should be held and appropriate therapy to treat the manic symptoms should be initiated.4243444546

Psychiatric effects reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included agitation (2% to 31.9%), anxiety (3.1% to 8%), memory impairment (less than 0.5 and up to 3% ), confusion (8.4%), delusions (1.2%), impaired concentration (3.1% to 9%), hostility (5.6%), irritability (2% to 3%), thinking abnormality (1%), and abnormal dreams (3% to 5%). These reactions may happen in patients treated for major depressive disorder (MDD) or in those who use bupropion for smoking cessation. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following psychiatric effects and incidences were reported: dysphoria (less than 1%, 1%, 2%, 1%), anxiety (8%, 6%, 9%, 6%), impaired concentration (9%, 3%, 9%, 4%), and abnormal dreams (5%, 18%, 13%, 3%). During other pre-marketing or postmarketing use, hallucinations and agitation occurred in 1% or more of patients. Memory impairment, depersonalization, psychosis, confusion, dysphoria, emotional lability, hostility, paranoia, formal thought disorder (unspecified), and frigidity were reported in 0.1 to 1% of patients. Amnesia and derealization occurred rarely (less than 0.1%). Also observed were aggression, delirium, delusions. Aggression, paranoia, and abnormal dreams have been reported during postmarketing use.4243444546

Depressive symptoms have been reported in smoking cessation studies as well as psychiatric studies with bupropion. During clinical trials for major depressive disorder, akathisia (psychomotor restlessness) was reported in 1.5% of bupropion-treated patients. Suicide attempt and completed suicide have occurred in 0.1% to 1% of patients during clinical trial evaluation or postmarketing use of bupropion. Mania can occur in predisposed patients during treatment with an antidepressant. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. A ten-year retrospective postmarketing safety review conducted by the FDA indicated that bupropion smoking cessation products were associated with 46 cases of suicidal ideation and 29 cases of suicidal behavior in patients with a prior psychiatric history (n = 18), without this history (n = 24), or an unknown psychiatric history (n = 33). In the cases of suicidal ideation for which demographics were available, 40% were male, 60% were female, and the median age was 46 years (range 26 to 70 years). In the cases reporting suicidal behavior, 59% were male, 41% were female, and the median age was 35 years (range 15 to 70 years). A significant change in thinking and/or behaviors was reported by 23% of the patients after treatment initiation. Seventy percent of the studied patients also had a diagnosis of depression. Of the cases considered serious (n = 59), outcomes were categorized as follows and were not mutually exclusive: death (17%), hospitalization (36%), life-threatening (27%), disability (8%), intervention required (3%), and other (31%). Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation.4542434446

Frequent neurological adverse events associated with bupropion include myoclonia. During clinical trials, the incidence of myoclonia in bupropion recipients was 1% or more. Patients with Gilles de la Tourette's syndrome or a family history of this syndrome may have motor or phonetic tics unmasked or exacerbated by the use of bupropion for ADHD symptoms. Exacerbation of tics may respond to dosage reduction; in some cases bupropion may need to be discontinued.4243444546

Bupropion may cause weight loss. A weight loss of more than 5 pounds occurred in 23.2% of patients taking immediate-release bupropion, approximately double that seen for patients on tricyclic antidepressants or placebo. Approximately 14% of patients on sustained-release formulations lose weight. Roughly 23% of patients receiving bupropion XL enrolled in seasonal affective disorder (SAD) trials had a weight loss of > 5 lbs. compared to 11% on placebo; alternatively 11% of bupropion XL patients had a weight gain > 5 lbs. compared to 21% on placebo. Weight gain may be associated with untreated depression. In general, weight gain is typically rare with bupropion treatment; across all formulations, weight gain occurred in 2—13.6% of bupropion recipients during clinical trials. It is not known if bupropion, like other ADHD therapies, causes growth inhibition in pediatric patients. The incidence of anorexia reported during trials was similar for patients taking bupropion and patients on placebo (roughly 1—18%) and may represent a symptom of the depressive illness rather than an adverse event. Although not as common, appetite stimulation (2—3.7%) was also reported following administration of bupropion during clinical trials.4243444546

Cardiac toxicity is relatively uncommon for bupropion when compared with tricyclic antidepressants. Hypertension occurred in 1—4.3% of patients taking bupropion during clinical trials, compared to 0—1.6% taking placebo. New onset or worsening of existing hypertension occurred in a higher percentage of patients (i.e., 6.1%) taking bupropion concurrently with nicotine transdermal systems (NTS) for smoking cessation; in some cases hypertension was severe. Other cardiovascular effects which occurred more frequently in those receiving immediate-release or extended-release bupropion formulations than placebo during clinical trials included: unspecified cardiac arrhythmias (5.3% vs 4.3%), dizziness (22.3% vs 16.2%), hypotension (2.5% vs 2.2%), palpitations (2—6% vs 0—2.2%), syncope (1.2% vs 0.5%), sinus tachycardia (10.8% vs 8.6%), chest pain (unspecified) (< 1% to 4% vs 1%), and flushing (1—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following cardiac effects and incidences were reported: hypertension (1%, < 1%, 2%, 0%), palpitations (2%, 0%, 1%, 0%), and chest pain (< 1%, 1%, 3%, 1%). Edema was reported in >= 1% of patients during pre-marketing evaluation of bupropion. Flushing was reported in <= 1% of patients. Cardiac effects reported in 0.1—1% of patients included unspecified chest pain, ECG abnormalities (premature beats and nonspecific ST-T changes), dyspnea, orthostatic hypotension, stroke, sinus tachycardia, and peripheral vasodilation. Pallor, phlebitis, syncope, and myocardial infarction occurred rarely (< 0.1%). Also observed were complete AV block, extrasystoles, and pulmonary embolism; however, the frequencies are unknown. Cardiac effects noted after overdose of bupropion as a single agent have included sinus tachycardia, ECG changes including QRS prolongation, and arrhythmias (unspecified). Hypotension has been reported after overdose of bupropion in conjunction with other medications.4243444546

Blurred vision affected 2—14.6% of bupropion-treated patients during clinical trials, compared to 2—10.3% taking placebo. Diplopia was reported in 2—3% of those receiving active drug versus 2% of those receiving placebo. During other pre-marketing or post-marketing use, blurred vision or diplopia was reported in > = 1% of patients. Other ocular effects that occurred in clinical trials or during post-marketing use included abnormal accommodation (0.1—1%), xerophthalmia (0.1—1%), ocular hypertension, and mydriasis.4243444546

During clinical trials of immediate-release or extended-release bupropion formulations, the following gastrointestinal effects and incidences compared to placebo included: dyspepsia (3.1% vs 2.2)), nausea (9—22.9% vs 8—18.9%), vomiting (2—22.9% vs 2—18.9%), diarrhea (4—7% vs 6—8.6%), constipation (5—26% vs 2—17.3%), xerostomia (10—27.6% vs 5—18.4%), hypersalivation (3.4% vs 3.8%), dysphagia (0—2% vs 0%), flatulence (6% vs 3%), abdominal pain (2—9% vs < 1—2%), and dysgeusia (2—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following GI effects and incidences were reported: nausea (9%, 7%, 11%, 4%), xerostomia (10%, 4%, 9%, 4%), constipation (8%, 4%, 9%, 3%), diarrhea (4%, 4%, 3%, 1%), oral ulceration (2%, 1%, 1%, 1%), abdominal pain (3%, 4%, 1%, 1%), dysgeusia (3%, 1%, 3%, 2%), and thirst (< 1%, < 1%, 2%, 0%). During other pre-marketing evaluations, stomatitis was reported in >= 1% of patients. Adverse digestive reactions occurring in roughly 0.1—1% of patients included teeth grinding (bruxism), elevated hepatic enzymes, jaundice, liver damage, excessive thirst (polydipsia), gastroesophageal reflux, gingivitis, glossitis, and hypersalivation. Rare events in < 0.1% of patients have included colitis, GI bleeding, GI perforation, and stomach ulcer. Digestive adverse reactions reported during post-marketing use of bupropion include esophagitis, gum bleeding, hepatitis, and pancreatitis. Due to the voluntary nature of post-market reports, neither incidence nor definitive association to bupropion can be established.4243444546

Twice as many patients taking bupropion reported libido decrease (3.1%) compared to patients taking placebo (1.6%). Conversely, libido increase has been reported in >= 1% of patients receiving bupropion. Menstrual irregularity was reported as unspecified menstrual complaints by 4.7% of patients and as dysmenorrhea (2% vs < 1% for placebo) and/or vaginal bleeding in 0—2% of patients vs < 0.5% of placebo-treated patients. Impotence (erectile dysfunction) occurred in 3.4% and painful erections occurred in 0.1—1% of bupropion recipients during clinical trials. Cases of gynecomastia, prostate disorder, and testicular swelling have been reported in 0.1—1% of bupropion-treated patients. Other sexual or reproductive system reactions have also occurred and include ejaculation dysfunction (0.1—1%, reported as retarded ejaculation or painful ejaculation), painful erection, dyspareunia (< 0.1%), salpingitis, and vaginal irritation (0.1—1%). Causal effect may be uncertain as trials were not always conducted with adequate controls.4243444546

Depending on the dosage form of bupropion used, hot flashes have been reported in 1—3% of patients; menopause was reported in < 0.1% of bupropion recipients during clinical trials.4243444546

During clinical trials of immediate-release or extended-release bupropion formulations, hyperhidrosis occurred more frequently in the bupropion groups than the placebo groups (5—22.3% vs 2—14.6%). Rash (unspecified) (3—8%), pruritus (2—4%), urticaria (1—2%), alopecia (>= 1%), and xerosis (2%) were other dermatologic adverse reactions commonly reported by recipients of bupropion. Acne vulgaris (0.1—1%), maculopapular rash (< 0.1%), hirsutism (< 0.1%), photosensitivity (0.1—1%), and exfoliative dermatitis have also occurred infrequently or rarely with bupropion use. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following dermatologic effects and incidences were reported: rash (4%, 3%, 3%, 2%), pruritus (3%, 1%, 5%, 1%), and urticaria (2%, 0%, 2%, 0%).4243444546

Some endocrine side effects have been reported during postmarketing use of bupropion. These rare endocrine-related side effects have included hyperglycemia, hypoglycemia, glycosuria, hyponatremia, and syndrome of inappropriate antidiuretic hormone (SIADH). Due to the voluntary nature of postmarketing reports, neither causality nor incidence can be established.4243444546

Hematologic and lymphatic effects reported with bupropion include infrequent cases of ecchymosis (0.1—1%). Anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia, and changes in the INR and/or PT have been noted; the incidence has not been reported. Causality has not been established.4243444546

Musculoskeletal events reported during clinical trials by patients receiving bupropion therapy included arthralgia (1—5% vs 1—3%), asthenia (2—4% vs 2%), myalgia (2—6% vs 1—3%), and muscle spasms (1.9% vs 3.2%). Other musculoskeletal adverse reactions reported during bupropion use include muscle twitching (1—2% vs < 0.5%), arthritis (0—3.1% vs 0—2.7%), neck pain (2% vs 0—1%), sciatica (< 0.1%), pain in extremity (3% vs 2%), and pain (unspecified) (2—3% vs 2%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following musculoskeletal effects and incidences were reported: myalgia (4%, 3%, 5%, 3), arthralgia (5%, 3%, 3%, 2%), and neck pain (2%, 1%, < 1%, 0%). Musculoskeletal effects reported in 0.1—1% of patients receiving bupropion during pre-marketing or post-marketing use included leg muscle cramps, back pain, inguinal hernia, and muscle twitching. Musculoskeletal chest pain was reported in <= 1% of patients and sciatica occurred rarely (< 0.1%). Arthralgia, myalgia, muscle weakness (myasthenia), and muscle rigidity with increased temperature and rhabdomyolysis have been reported during post-marketing use.4243444546

Rarely, anaphylactoid reactions characterized by symptoms such as rash, pruritus, urticaria (1% to 2%), angioedema, edema, chest pain, and dyspnea (1%) requiring medical treatment have been reported in clinical trials with bupropion. Most of these events occur in 0.1% to 0.3% or less of patients treated. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome (SJS), and anaphylactic shock associated with bupropion. A case of a serum sickness reaction has also been reported in the literature. Serum-sickness-like reactions consist of delayed hypersensitivity reactions, arthralgia, myalgia, pyrexia, and rash.4243444546 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of bupropion according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).109 Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Bupropion should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.110111

Infections (8—9% vs 6% for placebo) have been reported by bupropion recipients during clinical trials. The types of infection included upper respiratory tract infections (5—9%) (e.g., sinusitis (1—5%), pharyngitis (3—13%), bronchitis (2%), pneumonia (< 0.1%)), urinary tract infections (1%), pelvic infections (< 0.1%), and influenza (>= 2%). Symptoms reported during use of bupropion that may be associated with these infections included rhinitis (12%), epistaxis (2%), increased cough (1—4%), nasal congestion (>= 2%), sinus congestion (>= 2%), pharyngolaryngeal pain (>= 2%), malaise (< 0.1%), fever (1—2%), fever/chills (1.2%), and bronchospasm (< 0.1%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following effects and incidences were reported: rhinitis (12%, 11%, 9%, 8%), increased cough (3%, 5%, < 1%, 1%), pharyngitis (3%, 2%, 3%, 0%), sinusitis (2%, 2%, 2%, 1%), dyspnea (1%, 0%, 2%, 1%), and epistaxis (2%, 1%, 1%, 0%).4243444546

Adverse reactions reported by recipients of bupropion during pre-marketing or post-marketing use, and not discussed elsewhere in the monograph, include peripheral edema (0.1—1%), fatigue (5% vs 8.6% for placebo), dental pain (0.1—1%), drug-induced body odor (< 0.1%), facial edema (0.1—1%), and hair discoloration (< 0.1%). Facial edema was also reported in a comparative trial of sustained-release bupropion (Zyban) monotherapy (< 1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (1%), or placebo (0%).4243444546

Urinary tract reactions reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included increased urinary frequency (2—5% vs 2—2.2%), urinary urgency (< 0.5—2% vs 0%), urinary retention (1.9% vs 2.2%), and urinary tract infection (0—1% vs < 0.5%). Nocturia and urinary frequency occurred in >= 1% of patients during pre-marketing evaluation. Polyuria, urinary urgency, and prostate disorder were reported in 0.1—1% of patients. Cystitis and dysuria occurred rarely (< 0.1%). Also observed post-marketing were cystitis, dysuria, urinary incontinence, and urinary retention; however, the frequencies were not reported.4243444546

During clinical trials of immediate-release or extended-release bupropion formulations, the following extrapyramidal symptoms occurred in the bupropion groups at similar incidences to placebo: bradykinesia (8%), and pseudoparkinsonism (1.5%). Extrapyramidal syndrome (unspecified) has been reported during use of bupropion. Extrapyramidal symptoms that have occurred in 1% or more of patients during pre-marketing evaluation include dystonic reaction and dyskinesia. Hyperkinesis and hypertonia have been reported in 0.1% to 1% of patients. Akinesia, hypokinesia, dystonia, dyskinesia, pseudoparkinsonism, and unmasking of tardive dyskinesia have also occurred during postmarketing use; however, the incidences are unknown.4243444546

During clinical trials of immediate-release or extended-release bupropion formulation, tinnitus was reported more frequently in patients receiving bupropion than placebo (3—6% vs < 1% to 2%). Unspecified sensory disturbance (4% vs 3.2%), auditory or hearing disturbance (5.3% vs 3.2%), and gustatory disturbance (3.1% vs 1.1%) were also reported more frequently in active treatment groups than placebo groups. Tinnitus occurred during a comparative trial of sustained-release bupropion (Zyban) monotherapy (1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (< 1%), and placebo (0%). During pre-marketing or post-marketing use of bupropion, deafness (hearing loss) has been reported.4243444546

While not reported for bupropion, a neonatal abstinence syndrome has been reported in infants exposed to certain antidepressants in utero. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. In some reports, serum concentrations of the agent were measurable in the infants affected, so the symptoms may have been due to a direct adverse effect of the antidepressant. The physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, appropriate tapering of the agent prior to delivery may be considered as an alternative.4243444546

Euphoria was reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trial evaluation (1.2% vs. 0.5%). During controlled trials in patients with a history of multiple substance abuse, normal volunteers, and depressed patients, there was an increase in motor activity and agitation/excitement. In a single dose study of bupropion 400 mg in a population of individuals experienced with drugs of abuse, a mild amphetamine-like activity was produced as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability. Although use of recommended daily dosages of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers, higher doses (that could not be tested because of seizure risk) could theoretically be modestly attractive to those who abuse CNS stimulant drugs.43 In addition, the inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.45

In an ISMP safety report, bupropion was noted as 1 of the 19 overall drugs and one of the 9 antidepressants having the strongest signals for serotonin syndrome with 18 cases reported over 1 year to the FDA Adverse Event Reporting System (FAERS). Serotonin syndrome rarely happens with single drug therapy, and more commonly is reported with interactions between multiple serotonergic drugs or accidental or intentional drug overdoses.112 How bupropion might promote serotonergic excess is unclear, as bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase. The manufacturers have not reported serotonin syndrome as a postmarketing event. Phentermine HCl

Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients.36113114115

Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia.36113114115

Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.36113114115

Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.36113114115

Urticaria has been reported in patients receiving phentermine.36113114115

Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usual recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with intense psychological dependence and severe social dysfunction.11436113115 There are reports of patients who have increased the dosage of these drugs to many times than recommended. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommended.11436113115 Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal.116 More data are needed to confirm the dependence potential of phentermine-containing obesity products.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased. The maximum recommended dose should not be exceeded.36113114115