Bupropion HCl / Naltrexone HCl / Topiramate Capsules

Bupropion HCl

Bupropion is an oral antidepressant drug of the aminoketone class. It is not a tricyclic antidepressant and is unrelated to other known antidepressants. Bupropion has been well tolerated in patients experiencing orthostatic hypotension with tricyclic antidepressant drugs, however, it shows a greater potential for causing seizures than other antidepressants.1 Bupropion is also indicated for use as an aide to smoking cessation, and is used off-label for addiction to smokeless tobacco. The drug has been shown to help people with COPD quit smoking when combined with behavior modification. Bupropion is also used off-label for multiple neurological/psychological uses, including ADHD and neuropathic pain . Bupropion hydrochloride was originally approved by the FDA in December 1985 but was removed from marketing for several years due to concern over drug-induced seizures. It was reintroduced in July 1989 as an antidepressant (i.e., Wellbutrin), and later in a sustained-release formulation (i.e., Wellbutrin SR). Another sustained-release oral dosage form, Zyban, was approved for the management of smoking cessation in May 1997. Zyban received an additional indication for use in combination with nicotine transdermal systems (NTS) for treating the symptoms of smoking cessation in 1999. A controlled-release formulation (Wellbutrin XL) was approved in August 2003 as a once-daily formulation for major depression in adults. In June 2006, Wellbutrin XL was FDA-approved for prevention of major depressive episodes in patients with a history of seasonal affective disorder (SAD). Wellbutrin XL is the first prescription product approved for patients with a history of SAD. In April 2008, a once-daily formulation of bupropion hydrobromide (Aplenzin) was approved by the FDA for depression, and in August 2012 Aplenzin was approved for the prevention of seasonal major depressive episodes in patients with SAD. Aplenzin differs from all previously marketed formulations which are the hydrochloride salt of bupropion.

Naltrexone HCl

An oral opiate receptor antagonist is naltrexone. It is generated from thebaine and has a structure that is similiar to oxymorphone. Naltrexone is a pure antagonist, similar to parenteral naloxone (agonist activities are not visible), however it has a superior oral bioavailability and a significantly longer half-life than naloxone. In clinical settings, naltrexone is used to support individuals with a history of opiate dependence in remaining opiate-free. Patients who use naltrexone as part of a thorough occupational rehabilitation program or another program that increases compliance benefit most from it. Naltrexone does not support medication compliance and will not stop withdrawal, unlike methadone or LAAM. Naltrexone has been used as part of rapid and ultrarapid detoxification techniques. These techniques are designed to precipitate withdrawal by administering opiate antagonists. These approaches are thought to minimize the risk of relapse and allow quick initiation of naltrexone maintenance and psychosocial supports. Ultrarapid detoxification is performed under general anesthesia or heavy sedation. While numerous studies have been performed examining the role of these detoxification techniques, a standardized procedure including appropriate medications and dose, safety, and effectiveness have not been determined in relation to standard detoxification techniques. Naltrexone supports abstinence, prevents relapse, and decreases alcohol consumption in patients treated for alcoholism. Naltrexone is not beneficial in all alcoholic patients and may only provide a small improvement in outcome when added to conventional therapy. The FDA approved naltrexone in 1984 for the adjuvant treatment of patients dependent on opiate agonists. FDA approval of naltrexone for the treatment of alcoholism was granted January 1995. The FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation used to help control cravings for alcohol in April 2006, and then in October 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence after opioid detoxification.

Topiramate

An oral antiepileptic medication (AED) called topiramate is used to treat partial-onset, primary tonic-clonic seizures as well as Lennox-Gastaut syndrome. It differs structurally from other AEDs and is produced from the naturally occurring monosaccharide D-fructose. Topiramate appears to stop the spread of seizures rather than raising the threshold for seizures, in contrast to other AEDs. Topiramate has many mechanisms of action, which may help to explain why it is sometimes useful in treating patients with different types of seizures who have failed to respond to other medications. Infantile spasms linked to West syndrome are among the refractory epilepsies that are being explored in combination with other treatments as well as topiramate monotherapy. It is also used for migraine prophylaxis in adult and pediatric patients. There is some evidence of a role for topiramate treatment ‘off-label’ for eating disorders such as binge-eating disorder, for tics due to Tourette’s syndrome or other chronic tic disorders, or for substance abuse disorders such as alcohol dependence.

Bupropion HCl

Bupropion’s mechanism of action is not entirely understood. Bupropion is substantially more effective than imipramine or amitriptyline in this regard and selectively inhibits the neuronal reuptake of dopamine. Actions on dopaminergic systems, however, require doses higher than those needed for a clinical antidepressant effect. The blockade of norepinephrine reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. CNS-stimulant effects are dose-related. Bupropion does not inhibit monoamine oxidase or the reuptake of serotonin. Bupropion does exhibit moderate anticholinergic effects, and produces a sensation of mild local anesthesia on the oral mucosa. Antidepressant activity is usually noted within 1—3 weeks of initiation of bupropion treatment; full effects may not be seen until 4 weeks of therapy.

Unknown, but likely connected to reduction of noradrenergic or dopaminergic neuronal absorption, is how bupropion improves the capacity to stop smoking. The resulting rise in norepinephrine may lessen withdrawal symptoms from nicotine. Dopamine augmentation at neuronal locations may lessen the impulse to smoke and the need for nicotine. Because the onset of activity is usually after 1 week of treatment, patients should start bupropion 1—2 weeks prior to their chosen smoking ‘quit-day’. In smoking cessation, the ability to abstain from smoking continuously through the seventh week of bupropion therapy is associated with maintenance of long-term abstinence. Patients who have not stopped smoking by the seventh week of treatment are generally considered non-responsive to bupropion treatment.

Naltrexone HCl

Naloxone and naltrexone are both competitive antagonists at the mu, kappa, and delta opioid receptors. A panel of the International Union of Pharmacology has reclassified opiate receptors as OP1 (delta), OP2 (kappa), and OP3 (mu). Naltrexone either prevents opiate binding to these receptors or displaces opiate agonists from doing so. The effects of non-opiates like cocaine, ethanol, amphetamines, barbiturates, or benzodiazepines are not counteracted by naltrexone. The euphoric impact of opiates is eliminated as a result of naltrexone’s competitive blockade of opiate receptors. At usual opiate concentrations, naltrexone’s greater affinity for the receptor prevents the binding of the opiate agonist to the receptor. However, when opiate concentrations are extremely high, the opiate can displace naltrexone, and respiratory depression and/or death is possible. Although naltrexone itself may possess some agonistic properties, these are minor compared to its potent antagonistic actions. Naltrexone is 17-times more potent than nalmorphine and twice as potent as naloxone. In patients who are physically dependent on opiates, naltrexone will precipitate an opiate withdrawal syndrome. Naltrexone use is not associated with tolerance or dependence, therefore, withdrawal from naltrexone does not occur. When co-administered with opiate agonists, naltrexone blocks the physical dependence to morphine, heroin, and other opiate agonists. Depending on the dose, the clinical effects of naltrexone can persist for up to 72 hours.

Beta-endorphins and enkephalins, two examples of endogenous opiates, may be crucial in the development of alcoholism. To maintain a neutral state regarding the emergence of addiction, an opioid reward system mediated by mu- and delta-receptors and an opposing aversions system mediated by kappa-receptors must be in balance. Several theories regarding alcohol addiction and the function of endogenous opioids exist. All of these theories are based on an imbalance in favor of the endogenous reward pathways due to alcohol. Naltrexone inhibits the effects of endogenous opioids and decreases the positive or reward pathways associated with alcoholism. Naltrexone is not aversive therapy and will not produce a disulfiram-like reaction if opiates or ethanol are ingested while receiving naltrexone.

Topiramate

It is unknown how exactly topiramate works to prevent migraines and control seizures. Instead of lowering the threshold for seizures like other AEDs, topiramate seems to be able to prevent the spread of seizures. The medication seems to work through a number of different methods. Topiramate first shortens aberrant discharges by decreasing their duration and the quantity of action potentials they contain. This is most likely a byproduct of its capacity to obstruct sodium channels that are sensitive to voltage. Topiramate also increases the frequency at which the inhibitory neurotransmitter gamma-aminobutyrate (GABA) engages GABA-A receptors, which increases the activity of GABA at GABA-A receptors. Finally, topiramate blocks excitatory transmission by interacting negatively with specific glutamate receptor subtypes. Specifically, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor. There is no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. Topiramate is also a weak carbonic anhydrase inhibitor (isozymes II and IV); however, while this action can cause a risk for metabolic acidosis, this mechanism does not appear to be involved in the anticonvulsant action of the drug.

Topiramate has shown neuroprotective properties against hypoxic-ischemic brain damage in both in vitro and animal models, in addition to its effectiveness in the treatment of epilepsy and migraine prevention. Increased excitatory neurotransmitter release, especially glutamate, contributes to the cerebral damage caused by hypoxic-ischemic encephalopathy. Glutamate facilitates the elimination of the voltage-sensitive magnesium block on NMDA receptors by activating AMPA receptors, depolarizing the cell, and activating AMPA receptors. This, in turn, promotes the entry of calcium into the cell, stimulating a series of reactions that lead to cell necrosis and apoptosis. The neuroprotective properties of topiramate appear to be primarily related to its inhibition of the kainate/AMPA subtype of glutamate receptors. In addition, blockade of sodium channels, high-voltage calcium currents, carbonic anhydrase isoenzymes, and mitochondrial permeability transition pore (MPTP) may also contribute to its neuroprotective effects.

Bupropion HCl

IMPORTANT: Bupropion comes in a variety of dose forms, therefore in order to prevent dosing mistakes, it’s crucial to be familiar with the name, dosage, and dosing schedule of each product. Products containing bupropion, particularly the bupropion-naltrexone combination, shouldn’t be combined with other bupropion products. Bupropion replication can cause severe toxicity and seizures.

Those who have a history of hypersensitivity to bupropion or any inactive chemicals in the formulations should not take bupropion. Bupropion has been linked to delayed hypersensitivity reactions that have been described as arthralgia, myalgia, fever, and rash and may resemble serum sickness. There have also been reports of anaphylactoid/anaphylactic reactions, severe rashes, including Stevens-Johnson syndrome.

Bupropion is contraindicated in patients with a history of seizures or conditions that increase the risk of seizures, such as severe head injury, arteriovenous malformation, CNS tumors (such as brain tumors or intracranial masses), CNS infection, severe stroke, anorexia nervosa, bulimia nervosa, and abrupt benzodiazepine withdrawal, as well as abrupt withdrawal from alcohol, barbiturates, or anti-epileptic drugs. Other predisposing factors that may increase the risk of seizures include alcoholism, substance abuse (e.g., cocaine or prescription abuse of stimulants such as amphetamines), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, hypoxemia), diabetes mellitus treated with oral hypoglycemic agents or insulin, excessive use of benzodiazepines, sedative/hypnotics, or opiates, use of anorectic drugs for obesity treatment, or use of concomitant medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, tramadol, systemic corticosteroids). Bupropion should be discontinued and not re-initiated in patients who experience a seizure during treatment. The incidence of seizures with bupropion is dose-dependent. In studies using bupropion hydrochloride sustained-release up to 300 mg/day, the incidence of seizures was about 0.1%. The incidence of seizures in patients taking bupropion hydrochloride immediate-release 300 mg/day to 450 mg/day was about 0.4%. At higher immediate-release dosages between 450 mg/day and 600 mg/day, the estimated risk of seizures increases 10-fold compared to the seizure risk at 450 mg/day. The incidence of seizures has not been formally evaluated for the use of Aplenzin, Forfivo XL, or Wellbutrin XL. Do not exceed maximum recommended single or total daily dosages of any bupropion product. Patients who are taking bupropion for smoking cessation (e.g., Zyban) should not also take bupropion for depressive disorders (e.g., Wellbutrin, Aplenzin), and vice-versa. Healthcare professionals should be aware that bupropion is available under several brand names for various indications in order to avoid duplicative administration. During controlled trial evaluation of immediate-release bupropion, an increase in motor activity and agitation/excitement was demonstrated in normal volunteers, subjects with a history of multiple drug abuse, and depressed patients. Results from single-dose studies suggest that the recommended daily dose of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, because clinical trial results may not reliably predict the abuse potential of drugs, the benefits of treatment should be weighed against the potential for abuse prior to administering bupropion to patients with a history of substance abuse. It should be noted that bupropion extended-release formulations are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has resulted in seizures and/or cases of death.

The safety and efficacy of bupropion is not established in pediatric patients less than 18 years of age. Children 6 years and older with a major depressive episode or attention deficit hyperactivity disorder (ADHD) have been studied in clinical trials of bupropion, but data regarding pediatric safety are limited. Careful screening and monitoring is recommended by the American Heart Association if bupropion is used in pediatric patients. 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 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. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of bupropion may be necessary in patients with emerging suicidality or worsening depression.

Patients with Tourette’s syndrome or tics should be closely monitored for emerging or worsening tics during treatment with bupropion. Like other stimulant medications, bupropion may precipitate motor or phonetic tics in those with Tourette’s syndrome or a tic disorder.

In those who are vulnerable, the usage of antidepressants like bupropion has been linked to the emergence of mania or hypomania. Prior to starting an antidepressant, patients should undergo a thorough bipolar disorder screening that includes a thorough review of their personal and family histories of depression, bipolar disorder, and suicidal thoughts or behaviors. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of therapy and during dose adjustments. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality. If a patient develops manic symptoms, bupropion should be held, and appropriate therapy initiated to treat the manic symptoms. Patients should be observed for a potential psychiatric event or worsening of pre-existing psychiatric illness (e.g., schizophrenia, depression, bipolar disorder) during treatment with bupropion, including smoking cessation products (e.g., Zyban), due to serious neuropsychiatric symptoms reported during postmarketing use of bupropion products for smoking cessation. If neuropsychiatric symptoms develop, evaluate the patient for symptom severity and the extent of benefit from treatment, and consider dose reduction or discontinuation, or continued treatment with closer monitoring. In many cases, resolution of symptoms has occurred after discontinuation, although the symptoms can persist; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. Postmarketing reports during use of bupropion smoking cessation products have included neuropsychiatric adverse events such as mood or behavioral changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide in patients with and without a psychiatric history. Some reported cases may have been complicated by symptoms of nicotine withdrawal, such as depressed mood, in patients who stopped smoking. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Advise patients and caregivers that the patient should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, suicidal ideation, suicidal behavior, or other behavioral changes that are not typical for the patient are observed. The boxed warning in the bupropion smoking cessation product labeling regarding serious neuropsychiatric effects was removed in December 2016 following results from the Evaluating Adverse Events in a& Global Smoking Cessation Study (EAGLES), which was a large, randomized, double-blind, active- and placebo-controlled smoking cessation clinical trial assessing varenicline, bupropion, and nicotine replacement therapy in patients with (n = 4,003) and without (n = 3,912) a history of a psychiatric disorder. The results showed that the benefits of taking smoking cessation products outweigh the risks, which are less frequent and severe than previously suspected.

Bupropion should not be used in conjunction with MAOI medication for the treatment of psychiatric illnesses due to a higher risk of hypertensive responses. An MAOI used to treat psychiatric illnesses should be stopped at least 14 days before bupropion is started. Conversely, allow at least 14 days after stopping bupropion before starting an MAOI intended to treat psychiatric disorders. Starting bupropion in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate urgent treatment with linezolid or intravenous methylene blue in a patient taking bupropion. If acceptable alternatives are not available and benefits are judged to outweigh the risks of hypertensive reactions, bupropion should be promptly discontinued before initiating treatment with linezolid or methylene blue. Monitor the patient closely for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion may be resumed 24 hours after the last dose of linezolid or methylene blue. The risk of administering methylene blue by non-intravenous routes (e.g., oral tablets, local injection) or intravenous doses much less than 1 mg/kg with bupropion is unclear; however, clinicians should be aware that the potential for an interaction exists.

Bupropion should only be used during pregnancy if the possible benefit outweighs the potential harm to the developing fetus. The doctor should carefully weigh the benefits and dangers of the proposed course of treatment before administering it to a pregnant patient. If clinically possible, reducing the dosage before labor and opting for an obstetric delivery may be an option. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used; nicotine has been used in pregnancy to help patients quit smoking. Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce the risk for low birthweight and preterm birth. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations. In addition, no increased risk of cardiovascular malformations during first trimester exposure to bupropion has been observed. The rate of cardiovascular malformations following 675 exposures to bupropion in the first trimester was 1.3% versus a background rate of about 1%. Data collected from the United Healthcare database and the National Birth Defects Prevention Study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.

When administered to a breastfeeding woman, caution should be taken because bupropion and its metabolites are excreted in human breast milk. Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose. One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion. In two other cases, no infant-related adverse events were noted during breast-feeding. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. Because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Breast-feeding and eliminating an infant’s exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.

Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with hepatic impairment because a lower dosage strength is not available for use in this patient population. For other bupropion formulations, the dosage or dosage frequency should be reduced in patients with moderate to severe hepatic impairment (Child-Pugh Score 7—15). For patients with mild hepatic dysfunction (Child-Pugh Score 5—6), reduced dosage or dosage frequency should be considered; however, no specific guidelines are available. Monitor patients with any degree of hepatic disease carefully. Bupropion undergoes extensive hepatic metabolism and excretion in the urine as metabolites; there is a risk for accumulation in hepatic impairment. In addition, caution is advisable when using bupropion in patients with severe hepatic impairment because this condition can increase the risk of seizures.

Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with renal impairment since a lower dosage strength is not available for use in this patient population. Other bupropion products should be used with extreme caution in patients with renal disease or renal failure because the parent compound or active metabolites could accumulate. Consider reduced dosages in these patient populations based on the degree of organ impairment, and closely monitor for adverse reactions that could indicate high drug or metabolite levels.

Of roughly 6,000 patients in bupropion sustained-release studies for both smoking cessation and depression, 275 were 65 and over and 47 were 75 and over. Several hundred geriatric patients 65 years and older have also been studied (in depression) with the immediate-release formulation. Both initial and maintenance bupropion doses should be reduced in geriatric patients if hepatic or renal impairment or debilitating disease is present; multiple-dose pharmacokinetic studies have indicated the elderly may be at risk for bupropion and metabolite accumulation. It may be useful to monitor renal function in the elderly. Bupropion may also cause weight loss which may be significant for elderly or otherwise debilitated patients. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, follow the recommended duration of therapy per pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, sedation, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk of falls. Bupropion may increase seizure risk and activity in susceptible individuals. Before discontinuation, taper bupropion to avoid a withdrawal syndrome. Concurrent use of two or more antidepressants may increase the risk of side effects; in such cases, there should be documentation of expected benefits that outweigh the associated risks and monitoring for an increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

Rarely, bupropion may cause a fast or irregular heart beat or increases in blood pressure in some patients. It should be used with caution in patients with a recent history of acute myocardial infarction or unstable cardiac disease, including heart failure. Pharmacokinetic studies suggest that left ventricular dysfunction results in lowered metabolism and excretion of bupropion and its metabolites. Because treatment with bupropion can result in elevated blood pressure and hypertension, patients should have their blood pressure checked prior to bupropion initiation and periodically throughout treatment. Bupropion may be used in combination with nicotine transdermal systems (NTS) as an aide to smoking cessation. In clinical trials, new onset treatment-induced hypertension or exacerbation of existing high blood pressure occurred more commonly in patients using the combination bupropion-NTS therapy. In some cases the exacerbation of hypertension required discontinuation of bupropion treatment. Patients should quit tobacco smoking prior to initiating the nicotine therapy in the bupropion-NTS combination regimen to reduce the risk of unwanted cardiac side effects. Close blood pressure monitoring is recommended. Patients who are taking bupropion should not self-treat with OTC nicotine products; the bupropion-NTS combination should only be used under the prescription and advice of a health-care prescriber. When used as monotherapy, patients should schedule to stop tobacco smoking during the second week of taking bupropion. When bupropion is used for smoking cessation, it should be noted that cessation of tobacco smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline and warfarin due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. Bupropion has been used in children and adolescents for the treatment of attention-deficit hyperactivity disorder (ADHD). Sudden unexplained death has occurred in adults and pediatric patients receiving stimulants at standard dosages for ADHD. Although bupropion is not a stimulant medication, the American Heart Association recommends conducting a detailed patient and family history and physical examination prior to initiating any ADHD pharmacologic treatment, and obtaining a baseline electrocardiogram (ECG) is a reasonable addition to the initial evaluation. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication.

Patients should be warned to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how bupropion will affect them. Some patients have reported lower alcohol tolerance during treatment with bupropion; advise patients that the consumption of alcohol should be minimized or avoided; avoid ethanol intoxication.

Caution is recommended when prescribing bupropion to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

It is generally recommended to avoid abrupt discontinuation of antidepressants. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. Because Forfivo XL is only available in a 450 mg tablet, the manufacturer recommends using another bupropion formulation for tapering the dose prior to discontinuation.

Laboratory test interference has been reported with bupropion use. False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. The false-positive result is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

Naltrexone HCl

Those who are hypersensitive to naltrexone or any of the ingredients in the commercially available product should not take naltrexone. In 75:25 polylactide-co-glycolide (PLG), naltrexone is added at a concentration of 337 milligrams per gram of microspheres. Carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection make up the diluent. Because that all three of these medications have a similar structural makeup, naltrexone shouldn’t be administered to patients who have a history of naloxone or nalmefene hypersensitivity.

The use of naltrexone in patients with hepatic disease should be carefully considered due to the hepatotoxic effects of naltrexone and the potential for decreased clearance of naltrexone. Naltrexone does not appear to be hepatotoxic at recommended doses. However, the margin between a safe dose and a hepatotoxic dose appears to be five-fold or less. There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits. There are reports of hepatitis and significant hepatic dysfunction in association with exposure to naltrexone oral tablets and parenteral naltrexone. In patients treated with naltrexone tablets or injection who presented with elevated transaminases, other potential causes were often identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Opioid withdrawal does not typically manifest as clinically significant hepatic dysfunction, however, abruptly precipitated opioid withdrawal may lead to systemic sequelae including acute liver injury. Warn patients of the potential risk of hepatic injury and advise them to seek medical attention if they experience symptoms of acute hepatitis. Discontinue use of naltrexone if signs/symptoms of acute hepatitis occur.

Depression, suicide, attempted suicide and suicidal ideation have been reported in patients receiving naltrexone for the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions. Monitor alcohol and opioid dependent patients, including those taking naltrexone, for the development of depression or suicidal thinking. Inform families and caregivers of patients being treated with naltrexone to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.

Naltrexone is contraindicated in patients who are receiving opioid analgesics, partial opiate agonists (e.g., buprenorphine), those with current physiologic opioid dependence, and those in acute opioid withdrawal. Administration of naltrexone to these patients may precipitate an abrupt withdrawal severe enough to require hospitalization, and in some cases management in the intensive care unit. To prevent precipitation of withdrawal, patients should be opioid-free (including tramadol) for a minimum of 7—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. In every case, be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. Since the absence of an opiate drug in the urine is often not sufficient proof that a patient is opiate-free, a naloxone challenge should be done if there is any question of occult opioid dependence. 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). Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. A positive reaction to the naloxone challenge predicts a similar response to naltrexone. Use of naltrexone is contraindicated in an individual who fails the naloxone challenge test or who has a positive urine test for opioids.The naloxone challenge can be repeated in 24 hours. Assess patients treated for alcohol dependence for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone. Precipitated opioid withdrawal has 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.

If a painful procedure such as surgery is planned, then naltrexone should be discontinued 72 hours prior to the procedure. Patients should be abstinent from opiate analgesia for at least 7 days before restarting naltrexone.

Naltrexone treated patients who require emergent opiate analgesia may require the administration of large opiate doses to provide adequate pain control, which may increase the risk of deep or prolonged respiratory depression. A rapidly acting opiate agonist is preferred for emergent analgesia to limit the duration of respiratory depression. Non-opiate receptor mediated actions (i.e., histamine-mediated) may occur with the use of opiates and should be expected (e.g., facial swelling, itching, generalized erythema or bronchoconstriction). Other alternatives for emergent analgesia in patients taking naltrexone include the use of regional analgesia, conscious sedation, non-opiate analgesics, or general anesthetics.

Patients on naltrexone who attempt to counteract its antagonistic effects with high dosages of an opiate agonist run the risk of overdosing or poisoning, both of which can be fatal; incidences of opioid overdose with fatal results have been documented in patients who stopped taking their medication. The blockage caused by naltrexone can be overcome even if it has a protracted pharmacologic effect. Patients may respond to lower doses of opioids than they had previously used as the naltrexone blockade wears off and eventually disappears, which could result in life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Patients are at particular risk at the end of the dosing interval, after missing a scheduled dose or after discontinuing naltrexone treatment. Patients should be informed of the serious consequences of attempting to overcome the opiate blockade and that they may be more sensitive to lower doses of opiate agonists once naltrexone therapy is stopped. Advise patients to inform family members and those closest to them of this increased sensitivity and risk of overdose.

Naltrexone and its major active metabolite are excreted primarily by the kidney. Use caution in administering naltrexone to patients with renal impairment. Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with a creatinine clearance of 50—80 ml/minute. The disposition of naltrexone in patients with moderate to severe renal impairment has not been evaluated. Dosage adjustments may be necessary in patients with renal dysfunction.

Naltrexone is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. In some individuals, opiate antagonists have been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones, although the clinical significance is not known. In rat studies, there was an increase in early fetal loss and pseudopregnancy, and a decrease in pregnancy rate. There was no evidence of teratogenicity; however, rats do not form a significant amount of the major human metabolite, 6-B-naltrexol; therefore, the potential reproductive toxicity of 6-B-naltrexol in rats is not known. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice. When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown.

According to the manufacturer, naltrexone and its metabolite are excreted into human milk, and a decision should be made to discontinue breast-feeding or discontinue naltrexone, taking into consideration the importance of the drug to the mother. Animal studies have shown the potential for tumorigenicity. No reports describing the use of naltrexone during breast-feeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant. If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse deterrent during breast-feeding.

The safe use of naltrexone in neonates, infants, children, and adolescents < 18 years has not been established.

Naltrexone may cause dizziness (see Adverse Reactions). Tell patients about the importance of not driving or operating machinery until they know how this medicine will affect them.

Administer the extended-release injectable suspension of naltrexone cautiously to patients with thrombocytopenia, coagulopathy, or other bleeding disorders. Patients with thrombocytopenia, vitamin K deficiency, a coagulopathy (e.g., hemophilia), or receiving anticoagulant therapy should be monitored closely when given intramuscular naltrexone because bleeding can occur at the IM injection site. All steps to avoid hematoma formation are recommended.

Naltrexone extended-release injectable suspension (Vivitrol) is only for intramuscular administration; intravenous administration and subcutaneous administration should be avoided. The risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue (see Adverse Reactions). Proper administration techniques and patient selection are imperative (see Administration). Consider alternate treatment for patients whose body habitus (obesity) precludes a gluteal intramuscular injection with the provided needle. Women may be physiologically at higher risk for injection site reactions because of typically higher gluteal fat thickness, and in fact, post-marketing reports of injection site reactions occur primarily in females. Also, a variable depth of subcutaneous tissue exists between patients; the depth is dependent on the gender and weight of the patient.

Topiramate

Any patient who has a high sensitivity to topiramate or any of its ingredients should not use it. In post-marketing experience with topiramate, severe and potentially fatal exfoliative dermatologic reactions have been documented. Cross-sensitivity between antibiotic sulfonamides and nonantibiotic sulfonamides, such as topiramate, is controversial. Antibiotic sulfonamides contain an amine linked to a benzene ring (arylamine moiety), attached directly to the sulfonamide structure; this arylamine attached to the sulfonamide structure is believed to be the central pathogenesis of hypersensitivity reactions. Although topiramate is a simple sulfonamide, the sulfonamide structure is not directly connected to a ring structure, and it lacks an arylamine moiety. Some experts believe apparent cross-reactivity represents multiple concurrent and unlinked drug hypersensitivities in predisposed patients. Although cross-reactivity with sulfonamide antibiotics appears unlikely, precaution or complete avoidance of nonantibiotic sulfonamides in individuals whose previous reaction was serious and/or life-threatening or in those with multiple drug hypersensitivities may be prudent.

Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving topiramate closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed 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.

In patients with or without a history of seizures or epilepsy, withdraw topiramate gradually to minimize the potential for seizures or increased seizure frequency. In situations where abrupt discontinuation of topiramate is medically required, appropriate monitoring is recommended.

Those who are also on metformin and have metabolic acidosis should not take extended-release topiramate. Hyperchloremic, non-anion gap metabolic acidosis can be brought on by topiramate. Topiramate’s effects on reducing bicarbonate levels may be enhanced by diseases or treatments that increase the risk of patients developing acidosis, such as kidney illness, severe lung disease, status epilepticus, diarrhea, the ketogenic diet, or specific medications. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment. Also, the concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Avoid alcohol with topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression. Trokendi XR is contraindicated with recent ethanol ingestion or ethanol intoxication (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day.

Closely monitor patients (especially neonates, infants, and children) treated with topiramate for evidence of decreased sweating and increased body temperature, especially in hot weather. Use caution when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Oligohidrosis, infrequently resulting in hospitalization, has been reported in association with topiramate use. Some of the cases were reported after exposure to an ambient temperature increase. The majority of these reports have been in pediatric patients.

In patients receiving topiramate, hyperammonemia with and without encephalopathy has been seen. Individuals who have mitochondrial illness, which results in decreased hepatic mitochondrial activity, may be more susceptible to hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, consider hyperammonemic encephalopathy and measure an ammonia concentration.

According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If topiramate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.

Topiramate dosage adjustment is necessary for patients with renal impairment. Before dosing, obtain an estimated creatinine clearance in patients at high risk for renal disease (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease). In patients with renal insufficiency, a reduction in the topiramate dose is needed. In patients with renal failure receiving dialysis, a supplemental topiramate dose may be required; topiramate is removed by hemodialysis at a rate greater than in patients with normal renal function. Also, conditions that predispose patients to acidosis, such as renal disease, may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment.

Serious rash (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) has 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. Inform patients about the signs of serious skin reactions.

Topiramate is associated with an increased risk of bleeding. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulant therapy).

Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients against driving or operating machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.

Topiramate can cause fetal harm when administered to a pregnant woman. Consider the benefits and risks of topiramate in women of childbearing potential, particularly when it is being considered for conditions not usually associated with permanent injury or death. Counsel women of childbearing potential regarding the potential risk to the fetus from topiramate exposure, and consider alternative therapeutic options in women who are planning a pregnancy. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate and for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 18% to 25% in topiramate-exposed infants compared to 7% in infants exposed to a reference antiepileptic agent (AED) and 5% to 9% in those without antiepileptic drug (AED) exposure. The prevalence of oral clefts was 1.2% compared to 0.39% to 0.46% in infants exposed to another AED. The relative risk of oral clefts in topiramate-exposed pregnancies was 9.6 (95% CI 4 to 23) compared to untreated women. Oral clefts develop in the first trimester before many women know that they are pregnant. Pregnancy registry data also suggest a possible association between the use of topiramate during pregnancy and congenital malformations such as craniofacial defects, hypospadias, and anomalies of various body systems. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at http://www.aedpregnancyregistry.org or by calling 1-888-233-2334.

Topiramate is excreted in human breast milk. Diarrhea and somnolence have been observed in breastfed infants whose mothers received topiramate. The effects of topiramate on milk production are unknown. Consider the developmental and health benefits from breastfeeding along with the mother’s clinical need for topiramate and any potential adverse effects on the breastfed infant from topiramate or the underlying maternal condition. Data from 5 breastfeeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration. Based on breast milk concentrations from 3 women taking 150 to 200 mg topiramate daily, it was estimated that a breastfed infant (assuming a milk intake of 150 mL/kg/day) would receive approximately 0.1 to 0.7 mg/kg/day or 3% to 23% of the maternal weight-adjusted dose.

Topiramate is associated with reproductive risk. Discuss contraception requirements with the patient. Women of childbearing age who are not planning a pregnancy should use effective contraception because of the fetal risks of oral clefts and being small for gestational age.

Bupropion HCl

Bupropion should only be used during pregnancy if the possible benefit outweighs the potential harm to the developing fetus. The doctor should carefully weigh the benefits and dangers of the proposed course of treatment before administering it to a pregnant patient. If clinically possible, reducing the dosage before labor and opting for an obstetric delivery may be an option. Smokers who are expecting should be encouraged to try behavioral and educational therapies before turning to medication; nicotine has been used to help individuals stop smoking during pregnancy. Smoking cessation programs during pregnancy lower the percentage of women who smoke and lower the risk for preterm birth and low birthweight. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations. In addition, no increased risk of cardiovascular malformations during first trimester exposure to bupropion has been observed. The rate of cardiovascular malformations following 675 exposures to bupropion in the first trimester was 1.3% versus a background rate of about 1%. Data collected from the United Healthcare database and the National Birth Defects Prevention Study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.

Naltrexone HCl

FDA pregnancy risk category C is assigned to naltrexone. There are no sufficient and reliable research on expectant mothers. Opiate antagonists have been linked, but the clinical significance is unknown, to a shift in certain people’s baseline levels of certain hypothalamic, pituitary, adrenal, or gonadal hormones. There was a rise in early fetal loss and pseudopregnancy in rat trials, as well as a fall in the pregnancy rate. Nevertheless, since rats do not produce a sizable amount of the main human metabolite, 6-B-naltrexol, its potential reproductive harm is unknown. There was no evidence of teratogenicity. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice. When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown.

Topiramate

If topiramate is given to a pregnant woman, the fetus could suffer injury. When considering topiramate for illnesses that aren’t typically connected with mortality or permanent injury, take into account both the advantages and disadvantages for women who are or are planning to become pregnant. The potential danger of topiramate exposure to the fetus should be discussed with women of reproductive potential, and those who are contemplating a pregnancy should take other therapy choices into account. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate and for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 18% to 25% in topiramate-exposed infants compared to 7% in infants exposed to a reference antiepileptic agent (AED) and 5% to 9% in those without antiepileptic drug (AED) exposure. The prevalence of oral clefts was 1.2% compared to 0.39% to 0.46% in infants exposed to another AED. The relative risk of oral clefts in topiramate-exposed pregnancies was 9.6 (95% CI 4 to 23) compared to untreated women. Oral clefts develop in the first trimester before many women know that they are pregnant. Pregnancy registry data also suggest a possible association between the use of topiramate during pregnancy and congenital malformations such as craniofacial defects, hypospadias, and anomalies of various body systems. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at http://www.aedpregnancyregistry.org or by calling 1-888-233-2334.

Bupropion HCl

When given to a breastfeeding woman, care should be taken because bupropion and its metabolites are excreted in human breast milk. Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose. One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion. In two other cases, no infant-related adverse events were noted during breast-feeding. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. Because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Breast-feeding and eliminating an infant’s exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.

Naltrexone HCl

Since naltrexone and its metabolite are excreted in human milk, the manufacturer advises making a choice between stopping breastfeeding and stopping the medication, depending on how important it is to the mother. Animal studies have shown the potential for tumorigenicity. No reports describing the use of naltrexone during breast-feeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant. If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse deterrent during breast-feeding.

Topiramate

Human breast milk excretes topiramate. Infants who were breastfed and whose mothers had taken topiramate have shown signs of diarrhea and sleepiness. Topiramate’s impact on milk production is unknown. Together with the mother’s clinical requirement for topiramate and any potential negative effects on the breast-fed newborn from topiramate or the underlying maternal disease, take into account the developmental and health benefits of breastfeeding. Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration. Based on breast milk concentrations from 3 women taking 150 to 200 mg topiramate daily, it was estimated that a breast-fed infant (assuming a milk intake of 150 mL/kg/day) would receive approximately 0.1 to 0.7 mg/kg/day or 3% to 23% of the maternal weight-adjusted dose.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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