Bella Capsules

Side Effects

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. 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). 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.

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.

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.

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.

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.

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.

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.

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.

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.

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 established.

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.

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.

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%).

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 the incidence can be established.

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.

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.

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. 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). 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.

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%).

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%).

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.

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.

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.

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.

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.

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. 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.

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.

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

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

Urticaria has been reported in patients receiving phentermine.

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. 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. 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. 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.

Topiramate

Eleven percent of patients receiving topiramate 200 to 400 mg/day as adjunctive epilepsy therapy discontinued the drug due to adverse events. Of the 1,715 adult epileptic patients treated with topiramate at doses of 200 to 1,600 mg/day, 28% discontinued treatment because of adverse reactions which included sleepiness (3.2%), feeling dizzy (2.6%), balance issues (2.2%), paresthesia (2%), and language problems (2%). Side effects in pediatric patients at age and weight-adjusted dosages are similar to those of adults. Common adverse reactions reported in the monotherapy trials were similar to those reported in the adjunctive trials. Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following centrally-mediated effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: paresthesias (21% vs. 40%), dizziness (13% vs. 14%), hypoesthesia (4% vs. 5%), ataxia (3% vs. 4%), drowsiness (10% vs. 15%), and insomnia (8% vs. 9%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, paresthesias (3% vs. 12%), involuntary movements/muscle contractions (0% vs. 3%), and vertigo (0% vs. 3%) occurred in patients receiving topiramate 50 mg per day and 400 mg per day, respectively. In monotherapy clinical trials of topiramate 50 to 200 mg/day for the prophylaxis of migraines, the following CNS effects occurred more frequently with topiramate than placebo: paresthesias (35% to 51% vs. 6%), dizziness (8% to 12% vs. 10%), hypoesthesia (6% to 8% vs. 2%), language problems (6% to 7% vs. 2%), involuntary movements/muscle contractions (2% to 4% vs. 1%), ataxia (1% to 2% vs. < 1%), speech disorders/related speech problems such as dysarthria (<= 2% vs. < 1%), drowsiness (8% to 10% vs. 5%), and insomnia (6% to 7% vs. 5%). Dizziness (<= 6% vs. 4%), headache (2% to 8% vs. 2%), language problems (<= 15% vs. 2%), involuntary muscle contractions (<= 8% vs. 0%), insomnia (<= 9% vs. 2%), drowsiness (2% to 15% vs. 2%), and paresthesias (19% to 38% vs. 7%) were also reported during adolescent trials. Paresthesias, dizziness, drowsiness, and hypoesthesia were considered dose-related CNS effects. Aphasia (2%) and irritability (2%) were reported during adult adjunct therapy epilepsy trials. Other CNS effects reported during epilepsy clinical trials (monotherapy or adjunct therapy) in 0.1% to 1% of patients included peripheral neuropathy, apraxia, hyperesthesia, dysphonia, scotomata, ptosis, and EEG changes. Rare effects (< 0.1%) included upper motor neuron lesion, acute cerebellar syndrome, and tongue paralysis. During clinical trial evaluation of topiramate for the prophylaxis of migraines, headache, vertigo, tremor, sensory disturbance, and aggravated migraine were reported in > 1% of patients. Hyperkinesis (5%), hyporeflexia (2%), and grand mal seizures (1%) were reported in add-on epilepsy trials in pediatric patients.

All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior, depression, or other changes in mood/behavior. During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following psychiatric effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: difficulty with memory NOS (memory impairment) (6% vs. 11%), depression (7% vs. 9%), impaired concentration/attention (7% vs. 8%), anxiety (4% vs. 6%), psychomotor impairment (3% vs. 5%), emotional lability (2% vs. 5%), cognitive impairment (1% vs. 4%), and libido decrease (0% vs. 3%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 16 years of age, the following psychiatric effects were reported in patients in the 50 mg per day group vs. the 400 mg per day group: emotional lability (1% vs. 8%), impaired concentration/attention (7% vs. 10%), memory impairment (1% vs. 3%), cognitive impairment (1% vs. 6%), confusion (0% vs. 3%), depression (0% vs. 3%), and behavior problems (0% vs. 3%). In monotherapy adult clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following effects occurred more frequently in the active treatment groups than the placebo group: memory impairment (7% to 11% vs. 2%), impaired concentration/attention (3% to 10% vs. 2%), anxiety (4% to 6% vs. 3%), emotional lability (3% to 6% vs. 2%), depression (3% to 6% vs. 4%), nervousness (4% vs. 2%), confusion (2% to 4% vs. 2%), psychomotor impairment (2% to 4% vs. 1%), libido decrease (1% to 2% vs. 1%), worsening depression (1% to 2% vs. 1%), agitation (1% to 2% vs. 1%), and cognitive impairment (< = 2% vs. 1%). Anxiety (<= 8% vs. 0%), impaired concentration/attention (<= 15% vs. 0%), memory impairment (<= 8% vs. 2%), emotional lability (2% to 8% vs. 4%), and psychomotor impairment (<= 8% vs. 0%) were also prevalent in adolescent migraine trials; in addition, nervousness was reported in >= 2% of adolescents. Hallucinations, psychosis, and suicide attempt were reported in > 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Euphoria, paranoia, delusions, delirium, and abnormal dreaming were reported 0.1% to 1% of patients. Rare effects (< 0.1%) included libido increase and mania (manic reaction). Anticonvulsants, including topiramate, are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.

Hyperammonemia with and without encephalopathy has been reported with topiramate use and may be dose-related. In adolescent migraine prophylaxis trials, the incidence of hyperammonemia was 9% for placebo, 14% for topiramate 50 mg/day, and 26% for 100 mg/day. The incidence of markedly increased hyperammonemia (i.e., ammonia values at least 50% higher than the upper limit of normal) was 3% for placebo, 0% for topiramate 50 mg/day, and 9% for 100 mg/day; markedly abnormal concentrations returned to normal in all but 1 patient during the trial, in whom concentrations decreased to high instead of markedly abnormal. Although hyperammonemia can occur with topiramate monotherapy, it appears to be more common with adjuvant valproate therapy. Concomitant administration of topiramate and valproate may exacerbate existing metabolic deficits or unmask deficiencies in susceptible persons, and has been associated with hyperammonemia in patients who have tolerated either drug alone. Monitor serum ammonia concentrations in patients who develop unexplained lethargy, vomiting, changes in mental status, or hypothermia (i.e., an unintentional drop in core body temperature to < 35 degrees C), as these may be symptoms of hyperammonemic encephalopathy. Hypothermia may also occur in the absence of hyperammonemia.

Patients who develop unexplained symptoms of hyperammonemic encephalopathy or hypothermia while receiving antiepileptic therapy should discontinue the afflicting drug and receive prompt treatment for hyperammonemia, if present. In most cases, signs and symptoms abate with discontinuation of either topiramate or valproate.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following gastrointestinal (GI) effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: constipation (1% vs. 4%), gastritis (0% vs. 3%), xerostomia (1% vs. 3%), dysgeusia (3% vs. 5%), gastroesophageal reflux (1% vs. 2%), anorexia (4% vs. 14%), and weight loss (6% vs. 17%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, the following GI effects were reported in the 50 mg per day group vs. the 400 mg per day group: diarrhea (8% vs. 9%) and weight loss (7% vs. 17%). In monotherapy clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following GI effects occurred more frequently with topiramate than placebo: nausea (9% to 14% vs. 8%), diarrhea (9% to 11% vs. 4%), abdominal pain (6% to 7% vs. 5%), dyspepsia (3% to 5% vs. 3%), xerostomia (2% to 5% vs. 2%), vomiting (1% to 3% vs. 2%), dysgeusia (8% to 15% vs. 1%), taste loss (1% to 2% vs. < 1%), anorexia (9% to 15% vs. 6%), weight loss (6% to 11%), and gastroenteritis (2% to 3% vs. 1%). Dysgeusia (2% to 8% vs. 2%), abdominal pain (7% to 15% vs. 9%), diarrhea (2% to 8% vs. 0%), nausea (<= 8% vs. 4%), weight loss (4% to 31% vs. 2%), anorexia (9% to 15% vs. 4%), and pharyngeal edema (<= 8% vs. 0%) were reported in adolescent migraine trials; vomiting and gastroenteritis also occurred in >= 2% of patients. Gingivitis was observed in 1% of adult patients receiving topiramate during add-on epilepsy trials; in pediatric patients, hypersalivation (6%), fecal incontinence (1%), flatulence (1%), glossitis (1%), dysphagia (1%), weight gain (1%), appetite stimulation (1%), and gingival hyperplasia (1%) were observed. Other GI effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included hemorrhoids, stomatitis, melena, gastritis, esophagitis, taste loss, and gingival bleeding. Tongue edema was reported rarely (< 0.1%). During clinical trial evaluation of topiramate for migraine prophylaxis, constipation and gastroesophageal reflux were reported in > 1% of patients.

Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported for topiramate (4.5% adults and 4.4% pediatrics) than for placebo (3% adults and 2.3% pediatrics); serious bleeding events occurred in 0.3% vs. 0.2% of adult patients and 0.4% vs. 0% of pediatric patients for those treated with topiramate and placebo, respectively. Adverse events reported ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhage. In those with serious events, risk factors for bleeding were often present, or patients were taking other drugs that cause thrombocytopenia or affect platelet function or coagulation. During clinical trial evaluation of topiramate for migraine prophylaxis, epistaxis was reported in > 1% of adult patients and 2% to 8% of adolescent patients. In pediatric monotherapy trials for epilepsy, epistaxis was reported in 0% of patients receiving topiramate 50 mg per day and 4% of patients receiving 400 mg per day. Intractable epistaxis was reported in a 61 year old woman with cardiovascular disease who was receiving topiramate 25 mg daily for lower extremity neuropathy. Epistaxis developed 7 days after treatment initiation and resolved within 1 week of discontinuation. A rechallenge with topiramate 3 months later again resulted in epistaxis requiring 2 units of packed blood cells. According to the Naranjo probability scale, topiramate was the probable cause of epistaxis. Topiramate may modulate voltage-gated L type calcium ion channels located on vascular smooth muscle and non-contractile tissues such as platelets. During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, anemia was reported in 1% of patients receiving 50 mg per day and 2% of patients receiving 400 mg per day. In pediatric trials, anemia was reported in 1% of patients receiving 50 mg per day and 3% of patients receiving 400 mg per day. Leukopenia was reported in 1% to 2% of patients during add-on epilepsy trials in adults; in pediatric patients, thrombocytopenia (1%), purpura (8%), and hematoma (1%) were also observed. Deep vein thrombosis and thrombocytosis was reported infrequently (0.1% to 1%). Other hematologic effects reported rarely (< 0.1%) during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included bone marrow depression, lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia, and pancytopenia. Lymphocytosis and polycythemia were reported rarely (< 0.1%).

Rapidly evaluate any patient with symptoms of visual disturbance. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate who do not have a history of such conditions. Symptoms include acute onset of visual impairment and/or ocular pain. Ophthalmologic findings can include diplopia, myopia, blurred vision, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure (ocular hypertension). Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary closed-angle glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow-angle glaucoma, which is rare under 40 years of age, secondary closed-angle glaucoma associated with topiramate has been reported in children as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures in conjunction with discontinuation of topiramate may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. Visual field defects that are independent of elevated intraocular pressure have also been associated with topiramate therapy. These events are usually reversible following discontinuation of therapy. Consider discontinuing topiramate if visual problems occur. In monotherapy clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following ophthalmic effects occurred more frequently with topiramate than placebo: visual impairment (1% to 3% vs. < 1%), blurred vision (2% to 4% vs. 2%), and conjunctivitis (1% to 2% vs. 1%). Nystagmus was reported in 10% to 11% of adult patients during add-on epilepsy trials; in pediatric patients, abnormal lacrimation (1%) was also reported. Conjunctivitis was reported in > 1% of adult patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy; incidence rates were <= 7% in adolescent migraine trials. Abnormal accomodation, photophobia, xerophthalmia, and strabismus were reported in 0.1% to 1% of patients. Rare effects (< 0.1%) included mydriasis and iritis. During clinical trial evaluation of topiramate for migraine prophylaxis, abnormal accomodation and ocular pain were reported in > 1% of adult patients; visual impairment and ocular pain were present in >= 2% of adolescent patients. Maculopathy has occurred during post-marketing use.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following respiratory effects, infections, or related symptoms were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: viral infection (6% vs. 8%), infection (unspecified) (2% vs. 3%), bronchitis (3% vs. 4%), rhinitis (2% vs. 4%), and dyspnea (1% vs. 2%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, the following effects occurred in patients receiving topiramate 50 mg per day vs. 400 mg per day, respectively: fever (1% vs. 12%), viral infection (3% vs. 6%), infection (unspecified) (3% vs. 8%), upper respiratory tract infection (16% vs. 18%), rhinitis (5% vs. 6%), bronchitis (1% vs. 5%), and sinusitis (1% vs. 4%). In monotherapy clinical trials for migraine prophylaxis, the following effects occurred more frequently with topiramate 50 to 200 mg per day than placebo: fever (1% to 2% vs. 1%), influenza-like symptoms (< = 2% vs. < 1%), secondary malignancy (<= 2% vs. < 1%), viral infection (3% to 4% vs. 3%), upper respiratory tract infection (12% to 14% vs. 12%), sinusitis (6% to 10% vs. 6%), pharyngitis (2% to 6% vs. 4%), cough (2% to 4% vs. 2%), bronchitis (3% vs. 2%), dyspnea (1% to 3% vs. 2%), and rhinitis (1% to 2% vs. 1%). Adolescent migraine trials reported fever (<= 6% vs. 2%), viral infection (4% to 15% vs. 4%), otitis media (<= 8% vs. 0%), cough (<= 7% vs. 0%), laryngitis (<= 8% vs. 0%), rhinitis (6% to 8% vs. 2%), sinusitis (4% to 15% vs. 2%), and upper respiratory tract infection (23% to 26% vs. 11%); infection (unspecified), influenza-like symptoms, pharyngitis, bronchitis, and asthma occurred in >= 2% of adolescent migraine patients. Thrombocythemia and pulmonary embolism were reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Polycythemia was reported rarely (< 0.1%). During clinical trial evaluation for migraine prophylaxis, infection, genital candidiasis, pneumonia, and asthma (bronchospasm) were reported in > 1% of patients. Pallor (1%) has been reported in pediatric patients.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy, the following genitourinary (GU) effects were reported in adult patients receiving 50 mg/day vs. 400 mg/day, respectively: cystitis (1% vs. 3%), renal calculus or kidney stones (0% vs. 3%), urinary tract infection (1% vs. 2%), and increased urinary frequency (0% vs. 2%). In pediatric trials, increased urinary frequency (0% vs. 3%) and urinary incontinence (1% vs. 3%) were reported in patients receiving 50 mg/day vs. 400 mg/day, respectively. Urinary incontinence (1% to 2%) and hematuria (2% or less) were reported in adult patients during add-on epilepsy trials; in pediatric patients, urinary incontinence (1% to 4%) and nocturia (1%) were reported. In monotherapy clinical trials of 50 to 200 mg/day for migraine prophylaxis, the following GU effects occurred more frequently with topiramate than placebo: urinary tract infection (2% to 4% vs. 2%) and renal calculus (0% to 2% vs. 0%); adolescent migraine prophylaxis trials reported renal calculus (less than 1%), urinary incontinence (2% or more), and urinary tract infection (2% or more). Other GU effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included urinary retention, renal pain, albuminuria, polyuria, and oliguria. Topiramate has weak carbonic anhydrase inhibitor activity; carbonic anhydrase inhibitors promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials of topiramate as monotherapy epilepsy treatment, overall 1.3% of topiramate-treated adult patients developed nephrolithiasis; the incidence was slightly higher in adjunct therapy trials (1.5%). This incidence is about 2 to 4 times that expected in a similar, untreated population and was higher in men. In a long-term open-label epilepsy study in pediatric patients 1 to 24 months old, 7% developed kidney or bladder stones. The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation and should therefore be avoided. Instruct patients who are receiving topiramate and who have a history of kidney stones to increase their fluid intake in order to reduce the formation of kidney stones. Evaluate evidence of hematuria, dysuria, or crystalluria by renal ultrasound. Nephrocalcinosis has been observed with topiramate use during postmarketing experience.
Serious skin reactions (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) have been reported in patients receiving topiramate. Discontinue topiramate at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, do not resume topiramate use and consider alternative therapy. In a monotherapy epilepsy clinical trial in adults (16 years and older), the following dermatologic effects were reported in patients receiving topiramate 50 mg/day vs. 400 mg/day, respectively: rash (1% vs. 4%), pruritus (1% vs. 4%), alopecia (3% vs. 4%), and acne vulgaris (2% vs. 3%). In pediatric patients (6 to 15 years), alopecia (1% vs. 4%) and rash (3% vs. 4%) were reported in the 50 mg/day and 400 mg/day groups, respectively. Unspecified skin disorder was reported in 3% of pediatric patients (2 to 15 years) receiving topiramate in a placebo-controlled (2%), adjunctive epilepsy trials. In placebo-controlled adjunctive epilepsy trials in adults receiving topiramate 200 to 1,000 mg/day, hot flashes (1% to 2%), drug-induced body odor (0% to 1%), skin disorder (1% to 2%), hyperhidrosis (1% or less), and erythematous rash (1% or less) were reported with equal or greater frequency than placebo. In an adjunctive epilepsy trial in pediatric patients (2 to 16 years), skin disorder (3%), alopecia (2%), dermatitis (2%), hypertrichosis (2%), erythematous rash (2%), eczema (1%), seborrhea (1%), and skin discoloration (1%) occurred more frequently in topiramate-treated patients compared to patients given placebo. Pruritus was reported in 4%, 2%, and 2% of patients (including adolescents) receiving topiramate 50 mg/day, 100 mg/day, and 200 mg/day, respectively, for migraines in placebo-controlled (2%) clinical trials. Erythematous rash was reported in 8% of adolescents receiving topiramate 200 mg/day in pooled, double-blind migraine prophylaxis studies; however, it was not reported in adolescents receiving topiramate 50 or 100 mg/day. Pemphigus and bullous skin reactions (bullous rash), including erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported during postmarketing experience with topiramate.

Oligohidrosis and hyperthermia have been reported in association with topiramate use; heat stroke may occur. Oligohidrosis and hyperthermia have occurred primarily in children who were exposed to elevated environmental temperatures or were performing vigorous activity. Infrequent hospitalizations have occurred. To help prevent these adverse reactions in patients treated with topiramate, proper hydration is suggested before and during strenuous activity or exposure to warm temperatures. Use caution when topiramate is prescribed with other drugs that predispose patients to heat-related disorders, such as drugs with anticholinergic activity, carbonic anhydrase inhibitors, and zonisamide. Since topiramate exhibits carbonic anhydrase inhibitor activity, use with other carbonic anhydrase inhibitors is not recommended.

Topiramate is a weak carbonic anhydrase inhibitor and may lead to renal bicarbonate loss in a dose-dependent fashion. Hyperchloremic, non-anion gap, metabolic acidosis (hyperchloremic acidosis) is associated with topiramate. Metabolic acidosis due to topiramate is often asymptomatic. Measurement of baseline and periodic serum bicarbonate is recommended during topiramate therapy and prior to surgery. If metabolic acidosis develops and persists, consider a dosage reduction or discontinuation (using dose tapering). If the decision is made to continue topiramate despite persistent acidosis, alkali treatment should be considered. Bicarbonate loss is typically mild to moderate (roughly 4 mEq/L at an adult dose of 400 mg/day or a pediatric dose of 6 mg/kg/day) and tends to occur early in therapy, although cases can occur at any time. Rarely, bicarbonate loss may approach 10 mEq/L. Metabolic acidosis has been observed with doses as low as 50 mg/day. At doses of 400 mg/day in adjunctive epilepsy therapy trials, persistent reductions in serum bicarbonate < 20 mEq/L occurred at an incidence of roughly 32% vs. 1% placebo. Markedly abnormal serum bicarbonate (i.e., < 17 mEq/L and > 5 mEq/L reduction from baseline) occurred in 3% of topiramate-treated patients vs. 0% for placebo. In the monotherapy trials, the incidence of persistent decreases in serum bicarbonate in adults was 14% at doses of 50 mg/day and 25% for 400 mg/day. Markedly abnormal serum bicarbonate was observed in 1% of the 50 mg/day and 6% for the 400 mg/day adult group. During clinical trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in pediatric patients 2 to 16 years of age, persistent decreases in serum bicarbonate occurred in 67% of topiramate-treated patients and 10% of placebo-treated patients; 11% of topiramate-treated patients had markedly abnormal serum concentrations. The incidence of markedly abnormal changes in adults receiving topiramate for migraine prophylaxis was < 1% for placebo, 11% for 200 mg/day, 9% for 100 mg/day, and 2% for 50 mg/day. This incidence was similar in adolescent migraine prophylaxis trials; 2% for placebo, 2% for 50 mg/day, and 6% for 100 mg/day (criterion not met by the low number of patients [n = 13] in the 200 mg/day group). Although not FDA-approved in this population, a controlled trial in infants and children younger than 2 years demonstrated that the degree of metabolic acidosis caused by topiramate was notably greater in this population than that observed in trials of older children and adults. The incidence of metabolic acidosis (serum bicarbonate < 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day topiramate, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. The incidence of markedly abnormal changes was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day, and 5% for 25 mg/kg/day. Manifestations of metabolic acidosis, if symptomatic, may include: anorexia, cardiac arrhythmias, lethargy, hyperventilation, hypohidrosis, and stupor. Chronic metabolic acidosis may result in nephrolithiasis (renal stones), growth inhibition, osteomalacia, osteoporosis, and/or fractures. Some data in infants and toddlers with intractable partial seizures receiving topiramate showed reductions from baseline in z-scores for length, weight, and head circumference compared to age and sex-matched normative data; however, it should be noted that these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in z-scores for length and weight were correlated to the degree of acidosis.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, vaginal bleeding (hemorrhage) was reported in 0% of patients receiving 50 mg per day and 3% of patients receiving 400 mg per day. In pediatric trials, intermenstrual bleeding was reported in 0% and 3% of pediatric patients receiving 50 mg per day and 400 mg per day, respectively. Amenorrhea (2%) and menorrhagia (1% to 2%) were reported during add-on epilepsy trials. In monotherapy clinical trials for migraine prophylaxis, the following reproductive effects occurred more frequently with topiramate 50 to 200 mg per day than placebo: menstrual irregularity (menstrual disorder 2% to 3% vs. 2%) and ejaculation dysfunction (premature ejaculation 0% to 3% vs. 0%). Impotence (erectile dysfunction) was reported in > 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Ejaculation disorder and breast discharge were reported in 0.1% to 1% of patients. During clinical trial evaluation for migraine prophylaxis, intermenstrual bleeding was reported in > 1% of patients. Leukorrhea (2%) has been reported in pediatric patients.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, chest pain (unspecified) was reported in 1% of patients receiving 50 mg/day and 2% of patients receiving 400 mg/day. Edema (1% to 2%) and hypertension (2%) have been reported during add-on epilepsy trials. Other cardiovascular effects reported during epilepsy clinical trials (monotherapy or adjunct therapy) in 0.1% to 1% of patients included peripheral vasodilation, hypotension, orthostatic hypotension, AV block, and angina. During clinical trial evaluation of topiramate for migraine prophylaxis, chest pain was reported in > 1% of patients. Bradycardia (1%) has been reported in pediatric patients. Though the clinical significance has not been clearly established, notable changes (increases and decreases) from baseline in blood pressure and pulse rate were observed more commonly in pediatric patients treated with topiramate compared to those treated with placebo during migraine prophylaxis trials; these changes were often dose-related. The most notable changes were systolic blood pressure (SBP) < 90 mmHg, diastolic blood pressure (DBP) < 50 mmHg, SBP or DBP variation >= 20 mmHg, and pulse rate variation >= 30 beats per minute.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, hypertonia was reported in 0% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. Other extrapyramidal effects reported during clinical trials of topiramate as monotherapy or adjunct therapy of epilepsy in 0.1% to 1% of patients included dyskinesia and dystonic reaction.

During clinical trials of topiramate as migraine prophylaxis, polydipsia was reported in 1% to 2% of patients receiving 50 mg/day vs. < 1% of patients receiving 400 mg/day. Hyperthyroidism was reported in 8% of adolescent patients receiving 200 mg/day during migraine prophylaxis trials. Other metabolic or nutritional effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included dehydration, hypocalcemia, hyperlipidemia, hyperglycemia, and diabetes mellitus. Rarely reported effects (< 0.1%) included hypernatremia, hyponatremia, hypocholesterolemia, and increased creatinine. Hypoglycemia (1%) has been reported in pediatric patients. The clinical significance of various laboratory abnormalities observed during topiramate clinical trials has not been clearly established. For example, markedly decreased serum phosphorus (hypophosphatemia) (6%), markedly increased serum alkaline phosphatase (3%), and decreased serum potassium (0.4%) have also been observed during adult epilepsy trials. Additionally, BUN, creatinine, alkaline phosphatase, uric acid, total protein, platelets, and eosinophils were abnormally elevated more frequently in patients receiving topiramate compared to those receiving placebo in pediatric migraine prophylaxis trials. Phosphorus, total white blood cell count, and neutrophils were abnormally decreased in some subjects. Changes in several laboratory values (i.e., increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count, and decreased potassium) have been observed in children younger than 2 years treated with topiramate for partial onset seizures.

Vascular effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included flushing, deep vein thrombosis, and phlebitis. Vasospasm was reported rarely (< 0.1%). Flushing was also reported in 0% and 5% of patients receiving topiramate 50 mg per day and 400 mg per day, respectively, during pediatric monotherapy trials for epilepsy.

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, leg pain was reported in 2% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. In monotherapy clinical trials of topiramate 50 to 200 mg/day for migraine prophylaxis, arthralgia occurred more frequently with topiramate (1% to 7%) than placebo (2%). Musculoskeletal effects reported in at least 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included arthralgia (1% to 7%), leg muscle cramps (2%), and back pain (3% to 5%). Arthrosis (arthropathy) was reported infrequently (0.1% to 1%). During clinical trial evaluation of topiramate for migraine prophylaxis, myalgia was reported in > 1% of adult patients; myalgia, back pain, and pain (unspecified) were reported in >= 2% of adolescent patients.
During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, increased gamma-glutamyl transpeptidase (GGT) was reported in 1% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. Hepatic effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included elevated hepatic enzymes (ALT, AST). During post-marketing use, hepatic failure (including fatalities), and hepatitis have occurred; however, causality to the drug has not been established.

During topiramate epilepsy monotherapy trials, for daily doses of 50 mg vs. 400 mg, asthenia was reported in both adults (4% vs. 6%) and pediatric patients (0% vs. 3%). During migraine prophylaxis monotherapy trials, comparing topiramate 50 to 200 mg per day vs. placebo, the following were reported: fatigue (14% to 19% vs. 11%), injury (6% to 9% vs. 7%), asthenia (<= 2% vs. 1%), and allergy (<= 2% vs. < 1%); adolescent migraine trials also reported fatigue (7% to 15% vs. 7%). Syncope was reported in at least 1% of patients during epilepsy monotherapy or adjunct therapy trials. Enlarged abdomen, parosmia, and face edema were reported infrequently (0.1% to 1%), and alcohol intolerance was reported rarely (< 0.1%). During clinical trial evaluation for migraine prophylaxis, unspecified allergic reaction and pain were reported in > 1% of patients; leg pain was reported in 2% to 8% of adolescent patients. Pancreatitis has occurred during post-marketing use; however, causality to the drug has not been established.

During migraine prophylaxis monotherapy trials, tinnitus (<= 2% vs. 1%) and otitis media (1% to 2% vs. < 1%) were reported with topiramate 50 to 200 mg per day compared to placebo. Hearing loss occurred in 1% to 2% of patients during add-on epilepsy trials.

Naltrexone HCl

Naltrexone can cause hepatocellular injury when given in excessive doses. Naltrexone does not appear to be a hepatotoxin at the recommended doses. The hepatotoxic potential of naltrexone has been described in a placebo-controlled study using a 300 mg/day dose of naltrexone. In this study, 20% of patients experienced elevated hepatic enzymes (3—19 times baseline values). All patients were asymptomatic, and transaminase levels returned to baseline or decreased in a matter of weeks. Other studies of naltrexone doses > 50 mg/day in patients with opiate dependence or alcoholism also resulted in increased hepatic enzymes. Clinical trial data indicate that 7—13% of study patients receiving 380 mg of intramuscular naltrexone experienced elevated hepatic enzymes compared to 2—6% of those on placebo. Hepatitis, elevated hepatic enzymes, and hyperbilirubinemia have been reported in post-marketing reports with naltrexone. Warn patients of the risk of hepatic injury, and advise them to get immediate medical attention if they experience symptoms of acute hepatitis. A high index of suspicion for drug-related hepatic injury is critical if the occurrence of naltrexone-induced liver damage is to be detected at the earliest possible time. Evaluations to detect liver injury are recommended at a frequency appropriate to the clinical situation and to the naltrexone dose. Discontinue naltrexone if symptoms or signs of acute hepatitis develop.

Central nervous system (CNS) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence included headache (>= 7%), dizziness (4—9%), nervousness (>= 4%), insomnia (>= 3%), anxiety (>= 2%), fatigue (>= 4%), drowsiness (<= 2%), increased energy (< 10%), irritability (< 10%), paranoia (< 1%), restlessness (< 1%), confusion (< 1%), disorientation (< 1%), hallucinations (< 1%), nightmares (< 1%), yawning (< 1%), and hot flashes (< 1%). During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol opioid dependence, the following effects were reported more frequently with the active drug than placebo: dizziness or syncope (13% vs 4%), insomnia (6—14% vs 1—12%), headache (3—25% vs 2—18%), drowsiness (4% vs 1%), and anxiety (12% vs 8%). Cerebral arterial aneurysm, seizures, mental impairment, dysgeusia, euphoric mood (euphoria), migraine, ischemic stroke, irritability, disturbance in attention, abnormal dreams, agitation, delirium, hot flashes, and paresthesias were also reported during clinical trials of intramuscular naltrexone; however, the incidence of these effects is not known. CNS effects reported during post-marketing use of naltrexone include abnormal thinking, agitation, anxiety, headache, fatigue, confusion, euphoria, hallucinations, insomnia, nervousness, drowsiness, hot flashes, dizziness, and hyperkinesis. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.

Depression, suicidal ideation, and attempted suicide have been reported in individuals receiving oral naltrexone, placebo, and in concurrent control groups undergoing treatment for alcoholism and opiate dependence. In controlled clinical trials of the extended-release injectable suspension of naltrexone, suicidal ideation, suicide attempts, or completed suicides occurred in 1% of patients and in no patients treated with placebo. In some cases, the suicidal thoughts or behavior occurred after study discontinuation but were in the context of an episode of depression that began while the patient was taking naltrexone. Two completed suicides occurred in patients who were taking naltrexone. Depression-related events associated with premature discontinuation of naltrexone also occurred in about 1% of patients and in no patients treated with placebo. In the 24-week, placebo-controlled, pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with naltrexone 380 mg IM as compared with 5% of patients treated with placebo. Monitor patients for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality and to report such symptoms to the patient’s health care provider. Physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in patients.

In clinical trials of the extended-release injectable suspension of naltrexone, patients who took naltrexone had increases in eosinophil counts (eosinophilia) relative to patients on placebo, but eosinophil counts returned to normal over a period of several months in the patients who continued to take naltrexone. One diagnosed case and 1 suspected case of eosinophilic pneumonia occurred. The pneumonia resolved with antibiotics and corticosteroids. Consider eosinophilic pneumonia if progressive shortness of breath and hypoxia develop and if patients do not respond to antibiotics.

Patients treated with naltrexone 380 mg IM experienced a mean maximal decrease in platelet count of 17,800/mm3 as compared with 2600/mm3 in placebo patients. In randomized controlled trials, naltrexone administration was not associated with an increase in bleeding related adverse events. Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment. In addition, deep vein thrombosis and pulmonary embolism were reported as treatment-emergent adverse reactions during clinical trials of naltrexone suspension for injection; the incidences are unknown.

Gastrointestinal (GI) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence include nausea (>= 10%), vomiting (>= 3%), abdominal pain (> 10%), anorexia (< 10%), diarrhea (< 10%), constipation (< 10%), appetite stimulation (< 1%), weight loss (< 1%), weight gain (< 1%), xerostomia (< 1%), flatulence (< 1%), hemorrhoids (< 1%), and peptic ulcer (< 1%). During controlled trials of oral naltrexone 50 mg/day in alcohol dependence, approximately 5% of patients discontinued naltrexone due to nausea. During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol or opioid dependence, the following GI effects were reported more frequently with 380 mg of the active drug than placebo: nausea (33% vs 11%), vomiting (14% vs 6%), diarrhea (13% vs 10%), abdominal pain (11% vs 8%), xerostomia (5% vs 4%), dental pain (toothache 4% vs 2%), and anorexia (14% vs 3%). Weight loss, weight gain, abdominal discomfort, colitis, constipation, flatulence, appetite stimulation, gastroenteritis, gastroesophageal reflux disease (GERD), GI bleeding, hemorrhoids, acute pancreatitis, paralytic ileus, and perirectal abscess were also reported. In post-market experience of oral naltrexone, GI effects including anorexia, nausea, vomiting, abdominal pain, and diarrhea have been reported. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.

Injection site reactions have been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. Of 440 patients who received 380 mg of the extended-release injectable suspension of naltrexone (Vivitrol) in clinical trials for alcohol dependence, 69% had an injection site reaction (pain, tenderness, induration, swelling, or itching) versus 50% of those receiving a placebo injection. Specific injection site reactions that occurred more frequently in the active treatment group than the placebo group included injection site tenderness (45% vs 39%), injection site induration (35% vs. 8%), injection site pain (5% to 17% vs. 1% to 7%), nodules/swelling (15% vs. 4%), itching at the injection site (10% vs. 0%), and injection site ecchymosis (7% vs. 5%). One patient developed an area of induration at the injection site that continued to enlarge after 4 weeks. Eventually, necrotic tissue that required surgical excision developed. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and tissue necrosis. Sixteen patients required surgical intervention ranging from incision and drainage in the cases of abscesses to extensive surgical debridement in the cases that resulted in tissue necrosis. The extended-release injectable suspension of naltrexone should only be administered intramuscularly (IM); the risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue. Instruct patients to monitor the injection site and to get medical care if they develop pain, swelling, tenderness, induration, bruising, itching, or redness at the injection site that does not improve or worsens within 2 weeks. Promptly refer patients with worsening injection site reactions to a surgeon.

Urticaria, angioedema, and anaphylactoid reactions (anaphylaxis) have occurred in association with naltrexone administration in both clinical trials and during post-marketing use. Patients should be advised of the potential for serious hypersensitivity reactions while using naltrexone and instructed to seek immediate medical attention in the event of such a reaction.

During clinical trials using 380 mg of intramuscular (IM) naltrexone, infections reported more frequently within the active drug group than the placebo group included nasopharyngitis (7% vs 2%) and influenza (5% vs 4%). Other respiratory or related effects that were reported during IM naltrexone clinical trials included upper respiratory tract infection, advanced HIV disease in HIV-infected patients, bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, pharyngolaryngeal pain, pneumonia, sinus congestion, and sinusitis. Respiratory effects or symptoms of infection occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included nasal congestion, rhinorrhea, sneezing, sore throat, excess mucus, sinus trouble, hoarseness, cough, fever, and dyspnea. Additionally, eosinophilic pneumonia, which may present as dyspnea, coughing, and/or hypoxia, has been reported in association with injectable naltrexone use (see eosinophilic pneumonia).

In clinical trials of intramuscular naltrexone (380 mg) in patients with opioid dependence, 5% of study patients experienced hypertension compared to 3% of those on placebo. Other cardiovascular effects observed during clinical trials of intramuscular naltrexone included angina, atrial fibrillation, congestive heart failure, coronary artery atherosclerosis, myocardial infarction, and palpitations. Cardiovascular effects occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included epistaxis, phlebitis, edema, increased blood pressure, unspecified ECG changes, palpitations, and sinus tachycardia. Cardiac effects reported during post-marketing use of naltrexone include chest pain (unspecified), palpitations, and changes in blood pressure. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.

During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, the following musculoskeletal effects or pain symptoms were reported more frequently with the active drug than placebo: arthralgia (12% vs 5%), back pain (6% vs 5%), and muscle cramps (8% vs 1%). Myalgia, joint stiffness, limb pain, and muscle spasms have also been reported. Musculoskeletal effects or pain symptoms occurring during clinical trials of oral naltrexone for opiate dependence included arthralgia and myalgia (> 10%), shoulder pain (< 1%), knee or leg pain (< 1%), tremor (< 1%), twitching (< 1%), inguinal pain (< 1%), and side pain. Tremor and myalgia have been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome. Increased creatinine phosphokinase (CPK) concentrations have been associated with naltrexone use. In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. Increases in 1—2 times the upper limit of normal (ULN) were most common for both the oral naltrexone and IM naltrexone 380 mg groups. Although CPK elevations of 1—2 times ULN were most commonly encountered, elevations as high as 4 times ULN for the oral naltrexone group and 35 times ULN for the IM naltrexone group were noted. However, there were no differences between the placebo and either the oral or IM naltrexone groups with respect to the proportions of patients with a CPK value at least 3 times ULN. No factors other than naltrexone exposure were associated with the CPK elevations.

Dermatologic or related effects occurring during clinical trials of oral naltrexone for opiate dependence included rash (unspecified) (< 10%), oily skin (< 1%), pruritus (< 1 %), acne vulgaris (< 1%), tinea pedis (< 1%), cold sores (< 1%), and alopecia (< 1%). During clinical trials using 380 mg of intramuscular naltrexone suspension, rash occurred more frequently with active drug than placebo (6% vs 4%). Other related effects reported with the intramuscular formulation included night sweats, pruritus, heat exhaustion, and hyperhidrosis. Rash and increased sweating have also been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.

Genitourinary (GU) effects occurring during clinical trials of oral naltrexone included ejaculation dysfunction (delayed ejaculation < 10%), dysuria (< 1%), increased urinary frequency (< 1%), and libido increase or libido decrease (< 1%). Decreased libido and urinary tract infection have been reported with the use of the intramuscular formulation.

Special senses effects (otic, ophthalmic) occurring in less than 1% of patients during clinical trials of oral naltrexone included blurred vision, ocular irritation (burning), light sensitivity (photophobia), eye swelling/ache (ocular inflammation), otalgia, and tinnitus. Unspecified visual impairment has been reported during post-marketing use of oral naltrexone. Conjunctivitis and blurred vision have also been reported with the use of the intramuscular formulation. Retinal artery occlusion has been reported rarely after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during clinical trials or post-market use of the intramuscular formulation of naltrexone.

Lymphadenopathy and increased white blood cell count have been reported with the use of naltrexone extended-release suspension for injection during clinical trials.

Acute cholecystitis and cholelithiasis have been reported as treatment-emergent adverse effects in patients who received naltrexone extended-release suspension for injection for alcohol and/or opioid dependence; the incidence of these effects is unknown.

General effects occurring during clinical trials of oral naltrexone for opiate dependence included increased thirst (polydipsia) (< 10%), chills (< 10%), swollen glands (< 1%), and cold feet (< 1%). During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, asthenia was reported more frequently in the active treatment group than the placebo group (23% vs 12%). Other general events observed during clinical trial evaluation of intramuscular naltrexone included chest tightness, chills, face edema, pyrexia, rigors, and lethargy. Malaise and asthenia have been reported during post-market use of oral naltrexone.

During clinical trial evaluation of intramuscular naltrexone suspension, metabolic or nutritional effects including dehydration and hypercholesterolemia were observed; however, the frequencies are unknown. In some individuals, the use of opiate antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of these changes is not fully understood.

Abrupt withdrawal precipitated by administration of an opioid antagonist to an opioid-dependent patient may result in a withdrawal syndrome severe enough to require hospitalization, and in some cases management in the intensive care unit. Opioid withdrawal has been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. To prevent precipitation of withdrawal, patients should be opioid-free for a minimum of 7 to 10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. Precipitated opioid withdrawal has also been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. Studies of naltrexone in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid discontinuation-like symptom complex including, but not limited to, tearfulness, abdominal cramps, bone, muscle, or joint pain, nasal symptoms, and feeling restless. These symptoms may represent the unmasking of occult opioid use or it may represent symptoms attributable to naltrexone. Patients treated for alcohol dependence with naltrexone should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment. Because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period, prescribers should always be prepared to manage withdrawal symptomatically with non-opioid medications. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Withdrawal symptoms and death have been reported during the use of naltrexone in ultra rapid detoxification programs; the causes of death are not known. If rapid transition from agonist to antagonist therapy is considered necessary and appropriate by the healthcare provider, patients should be closely monitored in an appropriate medical setting where precipitated withdrawal can be managed.

Methylcobalamin

In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.

During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.

Diarrhea and headache.

Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.

Caffeine

Caffeine has been noted to produce a variety of gastrointestinal (GI) effects. At therapeutic or nontoxic doses, caffeine can stimulate gastric secretions and may cause GI upset (dyspepsia), nausea, loose stools, and may aggravate gastroesophageal reflux disease (GERD). Occasionally diarrhea is reported. The mild dehydration that caffeine produces may aggravate constipation. A temporary reduction in weight gain has also been reported. In a study comparing caffeine to placebo, the mean difference in weight gain was the greatest after 2 weeks of therapy. Feeding intolerance (8.7%), gastritis (2.2%), and GI bleeding (2.2%) also occurred in the caffeine treatment groups. During a controlled clinical trial of caffeine citrate in premature infants (n = 85 neonates), necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools, and lethargy in treated infants. Excessive caffeine intake or intoxication in children, adolescents, and adults may cause vomiting along with other signs of caffeine intoxication. In humans, a caffeine concentration of greater than 50 mg/L may produce toxic symptoms.

Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine’s pharmacologic actions. At therapeutic or nontoxic doses, caffeine can commonly cause nervousness, mild tremor, and heightened attentiveness. Less frequent adverse reactions with usual consumption also include excitement, irritability, insomnia, headache, and muscle twitches. Increased caffeine use among children and adolescents has been associated with insomnia, chronic headache, motor tics, irritability, learning difficulties, and other adverse health effects. After excessive doses, caffeine can cause considerable anxiety. Seizures and delirium are also possible. In humans, a caffeine level of > 50 mg/L may produce toxic symptoms. Other neurologic events have been reported in preterm neonates. In clinical trials of caffeine citrate in preterm neonates, cerebral hemorrhage (intracranial bleeding) was reported in 2.2% of treated patients versus 0% of neonates receiving placebo.

Caffeine is a mild diuretic and patients may have increased urinary frequency. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.

Adverse events to caffeine that have been described in the published literature include alterations in serum glucose such as hypoglycemia and hyperglycemia.

In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury (2.2%), bleeding (2.2%), disseminated intravascular coagulation (2.2%), dyspnea (2.2%), pulmonary edema (2.2%), metabolic acidosis (2.2%), xerosis (2.2%), rash (unspecified) (8.7%), renal failure (unspecified) (2.2%), retinopathy of prematurity (2.2%), and skin breakdown (2.2%). In neonates, intolerance or overdose of caffeine may manifest as tachypnea. No deaths have been reported in relation to overdose of caffeine in neonates.

Too much caffeine may occasionally cause rapid heartbeat. Cardiovascular effects of caffeine have been reported in the literature (i.e., palpitations, sinus tachycardia, increased left ventricular output, and increased stroke volume).

High caffeine intake has been reported to negatively affect sperm quality, including spermatogenesis inhibition). The propensity for caffeine to negatively affect fertility is controversial. Although controversial, infertility, as manifested by increased difficulty in getting pregnant, has been reported in females. Couples who are pursuing pregnancy should probably limit excessive intake of caffeine.

A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or rebound headache upon caffeine withdrawal.

Oxytocin

Some patients can experience a hypersensitive uterine reaction to the effects of oxytocin. Excessive doses can have the same effect. This can produce increased, hypertonic uterine contractions, possibly prolonged, resulting in a number of adverse reactions such as cervical laceration, postpartum hemorrhage, pelvic hematoma, and uterine rupture.

Oxytocin-induced afibrinogenemia has been reported; it results in increased postpartum bleeding and can potentially be life-threatening. Neonatal retinal hemorrhage has been reported. Also, intracranial bleeding including subarachnoid hemorrhage has been reported in patients receiving oxytocin. In one case, subarachnoid hemorrhage mimicked acute water intoxication and delayed the diagnosis of hemorrhage after an oxytocin assisted labor.

Adverse maternal cardiovascular effects from oxytocin may include arrhythmia exacerbation, premature ventricular contractions (PVCs), and hypertension. In the fetus or neonate, fetal bradycardia, PVCs, and other arrhythmias have been noted.

Oxytocin has an antidiuretic effect, and severe and fatal water intoxication has been noted and may occur if large doses (40—50 milliunits/minute) are infused for long periods. For example, water intoxication with seizures and coma has occurred in association with a slow oxytocin infusion over a 24-hour period. Management of water intoxication includes immediate oxytocin cessation and supportive therapy. In the fetus or neonate, fetal death, permanent CNS or brain damage, and neonatal seizures have been noted with oxytocin. The rare complications of blurred vision, ocular hemorrhage (of the conjunctiva), and pulmonary edema have been associated with oxytocin induced water intoxication.

Oxytocin administration has been associated with anaphylactoid reactions.

Oxytocin-induced labor has been implicated in an increased incidence of neonatal hyperbilirubinemia, about 1.6 times more likely than after spontaneous labor. This can lead to neonatal jaundice.

Nausea and vomiting have been noted with oxytoxin.

Side effects that you should report to your doctor or health care professional as soon as possible:

• allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
• breathing problems
• excessive or continuing vaginal bleeding
• fast, irregular heartbeat
• feeling faint or lightheaded, falls
• high blood pressure
• seizures
• unusual bleeding or bruising
• unusual swelling, sudden weight gain

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

• headache
• nausea and vomiting

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Metformin

Possible side effects include: Diarrhea; headache; heartburn; metallic taste in mouth; nausea; stomach gas, upset. This list may not describe all possible side effects. Call your doctor for medical advice about side effects.

Gastrointestinal adverse effects are the most common experienced by patients taking metformin. In clinical trials, diarrhea was experienced by 53.2% of patients receiving immediate-release metformin monotherapy, and was a reason for drug discontinuation in 6%. Extended-release formulations cause diarrhea in roughly 9.6% of patients. Nausea and vomiting are reported in 6.5—25.5% of all patients taking metformin; with the lower incidences seen in patients receiving extended-release products. Other common GI effects include flatulence (1—12.1%), indigestion or dyspepsia (1—7.1%), and abdominal pain or discomfort (1—6.4%). GI effects occurring in 1—5% of patients include include anorexia, dysgeusia (metallic taste or other taste disturbance), and a change in stool appearance. Frequent side effects tend to decline with continued use and can be minimized by initiating therapy with low doses of metformin. In pediatric patients with diabetes mellitus type 2 treated with metformin, the adverse event profiles and incidences are similar to those seen in adults.

The risk of hypoglycemia is much less common with metformin than with the sulfonylureas, however, it has been reported with metformin monotherapy in clinical trials at an incidence of 1—5%. Other studies have reported varying incidences of hypoglycemia. In one nested case-control analysis of over 50,000 subjects with type 2 diabetes mellitus, the rate of hypoglycemia due to metformin monotherapy yielded a crude incidence rate of 3.3 cases among 100,000 person-years compared with 4.8 cases among sulfonylurea users per 100,000 person years; the incidence of hypoglycemia was significantly higher in sulfonylurea-treated patients. In a separate systematic review, the rates for hypoglycemia with metformin monotherapy varied in the studies reviewed between 0—21%, with the risk of major hypoglycemic episodes reported to be rare. Hypoglycemia is more common when metformin is coadministered with other oral hypoglycemic agents (especially sulfonylureas), when ethanol has been ingested, or when there is deficient caloric intake or strenuous exercise not compensated by caloric supplementation. Since metformin reverses insulin resistance, and subsequently causes a decrease in insulin concentrations, metformin-induced hypoglycemia is usually mild and does not necessitate the discontinuation of therapy. In overdose, hypoglycemia is noted in roughly 10% of patients, but causal association with metformin is not established.

Asymptomatic vitamin B12 deficiency was reported with metformin monotherapy in 7% of patients during clinical trials. Serum folic acid concentrations did not decrease significantly. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin treatment or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful. Rare cases of megaloblastic anemia have been reported with metformin (none in the US); incidence rates are expected to be < 1% for symptomatic deficiency.

Mild weight loss may occur during therapy with metformin, perhaps as a result of its ability to cause anorexia. Such weight loss can be expected in almost any patient with type 2 diabetes receiving metformin monotherapy; however, weight loss may attenuate when metformin is combined with other treatments. A mean weight loss of 1—8.4 lbs was reported in clinical trials of adults receiving monotherapy with metformin immediate release products; a mean weight loss of 2—3 lbs was reported in pediatric studies. When extended-release tablets were used, the weight loss was not clinically significant in adults and mean reductions ranged from 0.7—2.2 lbs.

Lactic acidosis is a rare, but serious, form of metabolic acidosis that can occur if metformin accumulates during treatment; when it occurs, it is fatal in approximately 50% of cases. The onset of lactic acidosis often is subtle, and accompanied only by early nonspecific symptoms such as malaise and myalgia (1—5% of patients), and quickly followed by respiratory distress (dyspnea 1—5%), increasing somnolence, and nonspecific abdominal distress. Lactic acidosis is a medical emergency that must be treated in a hospital setting; metformin should be discontinued immediately and general supportive measures promptly instituted. Prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked metabolic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years); of nearly 20,000 patients in clinical trials, there were no reports of lactic acidosis. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis; all of the subjects had relevant co-morbidities known to be risk factors for lactic acidosis. The incidence of lactic acidosis appears to be no more common in metformin recipients without comorbid conditions than in recipients of other antidiabetic agents. Risk factors include significant renal insufficiency, the presence of multiple concomitant medical/surgical problems (e.g., liver disease, alcoholism, cardiorespiratory insufficiency or other conditions associated with tissue hypoperfusion or hypoxemia), and exposure to multiple concomitant medications known to increase risks. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. Lactic acidosis is less likely to occur with metformin than with other biguanide agents (e.g., phenformin), because metformin is not metabolized, does not bind to liver or plasma proteins, and is excreted by active tubular processes. Regular monitoring of renal function and by use of the minimum effective dose of metformin may reduce the risk of this adverse reaction. Patients should be informed to discontinue metformin should symptoms suggestive of lactic acidosis appear and promptly report the symptoms to their physician.

The following miscellaneous adverse reactions were reported in 1—5% of patients treated with metformin and occurred more commonly than in patients treated with placebo: lightheaded (dizziness), nail disorder, rash (unspecified), hyperhidrosis (sweating increased), chest pain (unspecified) or chest discomfort, chills, flu syndrome or upper respiratory infection, flushing, and palpitations.

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.