Phentermine HCl / Topiramate Capsules

Phentermine

Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a ‘Dear Health Care Professional’ letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.^[1]

Topiramate

Topiramate is an oral antiepileptic drug (AED) used for partial-onset, generalized primary tonic-clonic seizures, and as an adjunct therapy in Lennox-Gastaut syndrome. It is derived from the naturally occurring monosaccharide D-fructose and is structurally different from other AEDs. Unlike other AEDs, topiramate appears to block the spread of seizures rather than raise the seizure threshold. Topiramate possesses more than one mechanism of action, which may explain why it can be effective in patients with various seizures that are refractory to other agents. Topiramate continues to be studied as both add-on therapy and monotherapy in various refractory epilepsies in children and adults, including infantile spasms associated with West syndrome. 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.^{[2][3][4][5][6][7][8][9][10]}

Phentermine

Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic.^[11] Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself.^[12] Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct stimulation of the satiety center in the hypothalamic and limbic region.

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.

Topiramate

The exact mechanism of topiramate’s anticonvulsant and migraine prophylaxis effects is unknown. It appears that topiramate may block the spread of seizures rather than raise the seizure threshold like other AEDs. The drug appears to have several mechanisms of action. First, topiramate reduces the duration of abnormal discharges and the number of action potentials within each discharge. This is probably secondary to its ability to block voltage-sensitive sodium channels. Second, topiramate enhances the activity of the inhibitory neurotransmitter gamma-aminobutyrate (GABA) at GABA-A receptors by increasing the frequency at which GABA activates GABA-A receptors. Third, topiramate inhibits excitatory transmission by antagonizing some types of glutamate receptors. 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.^[2][3][4]

In addition to its efficacy in epilepsy and migraine prophylaxis, topiramate has also demonstrated neuroprotective effects against hypoxic-ischemic brain damage in both in vitro and animal models. The cerebral damage of hypoxic-ischemic encephalopathy occurs in part due to an increased release of excitatory neurotransmitters, including glutamate. Glutamate activates AMPA receptors, depolarizes the cell, and promotes the removal of the voltage-sensitive magnesium block on NMDA 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.^[13]

Phentermine

Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity.^[19][20]

According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease, advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma.^[21] Likewise, orally disintegrating tablets, are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension.^[20] Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further, primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity 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 lower extremity edema.

Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease.

Phentermine is contraindicated for use during or within 14 days following the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine.^[19]

Phentermine is contraindicated in patients with agitated states.aggravate these effects or cause an adverse drug reaction.^[19] Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety.

The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction.^[19] Advise patients to avoid alcohol while taking phentermine.

Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should monitor their blood glucose regularly and follow the recommendations of their health care provider.^[20]

Appetite suppressant therapy is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is chemically and pharmacologically related to the amphetamines which have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.^[20]

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.^[20][21] Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.^[21]

Abrupt discontinuation of phentermine after prolonged high doses may result in severe mental depression or extreme fatigue; sleep EEG changes have also been noted. Gradual withdrawal of therapy is recommended. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted.^[19]

Phentermine is contraindicated during breastfeeding.^[20] It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.^[22][21]

Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates.^[19][20]

The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal impairment.^[19]

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation.

Topiramate

Topiramate is contraindicated for use in any patient hypersensitive to the drug or any of the product components. Serious and potentially fatal exfoliative dermatologic reactions have been reported in post-marketing experience with topiramate.^[2][3] Cross-sensitivity between antibiotic sulfonamides and nonantibiotic sulfonamides, such as topiramate, is controversial.^[23] 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.^[23][24] Although topiramate is a simple sulfonamide, the sulfonamide structure is not directly connected to a ring structure, and it lacks an arylamine moiety.^[23][25] Some experts believe apparent cross-reactivity represents multiple concurrent and unlinked drug hypersensitivities in predisposed patients.^[26][24] 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.^{[26][23][24][25]}

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.^[2][3][4]

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.^[2][3][4]

Extended-release topiramate is contraindicated in patients with metabolic acidosis who are taking concomitant metformin. Topiramate can cause hyperchloremic, non-anion gap metabolic acidosis. Conditions or therapies that predispose patients to acidosis, such as kidney disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or certain drugs, 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. 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.^[2][3][4]

Avoid alcohol with topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression.^[4] 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.^[3]

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.^[27][3][4]

Hyperammonemia with and without encephalopathy has been observed in patients who were taking topiramate. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity (mitochondrial disease) may be at an increased risk for 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.^[2][28][4]

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.^[29] 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.^[30]

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.^[2][3][4]

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.^[2]

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).^[2][3][4]

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.^[2][3][4]

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.^[3] 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.^[2][3] Oral clefts develop in the first trimester before many women know that they are pregnant.^[31] 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.^[2][3] 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.^[3]

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.^[3] Data from 5 breastfeeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration.^[2] 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.^[32]

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.^[3]

Phentermine

The safety of phentermine when used with other anorexiant agents such as amphetamine, benzphetamine, dexfenfluramine, dextroamphetamine, diethylpropion, ephedrine, fenfluramine, and sibutramine^[33] is controversial and concurrent use should be avoided. The role of phentermine in the production of cardiac valvulopathy when combined with dexfenfluramine, fenfluramine, or other medications for weight loss is uncertain. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. Similarly, because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant)^[34] it should not be used in combination with other sympathomimetics or psychostimulants for weight loss, including OTC preparations, and herbal products that may contain ephedra alkaloids or Ma huang.

Phentermine, which increases catecholamine release, can increase blood pressure;^[35][34] this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.

Concurrent use of bromocriptine and some sympathomimetics such as phentermine should be approached with caution. One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen; dichloralphenazone; isometheptene for a headache.^[36] A second case involved a post-partum patient receiving bromocriptine who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm.^[36]

In theory, an interaction is possible between cabergoline, an ergot derivative, and some sympathomimetic agents such as phentermine. Use of the ergot derivative bromocriptine for lactation suppression in conjunction with a sympathomimetic (i.e., isometheptene or phenylpropanolamine) for other therapeutic uses has resulted in adverse effects such as worsening headache, hypertension, ventricular tachycardia, seizures, sudden loss of vision, and cerebral vasospasm.^[36]

Concurrent use of dronabinol, THC or nabilone^[37] with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity.^[38]

Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone, linezolid, or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phenelzine and tranylcypromine appear to produce the greatest risk since these two MAOIs also have intrinsic amphetamine-like activity. In the presence of MAOIs, phentermine and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. It is unclear if selegiline, an inhibitor of MAO type B, can also predispose to this reaction. Phentermine should not be administered during or within 14 days following the use of most MAOIs or drugs with MAO-inhibiting activity.^[34] Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected.^[39] However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics.

The pressor response to some sympathomimetics is exaggerated in patients currently receiving tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics, including phentermine, should be avoided whenever possible.^[40][11]

Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as guanadrel, guanethidine, methyldopa or reserpine.^[34] Phentermine may displace guanethidine from the neuron and antagonize the neuronal blockade caused by guanethidine. Concomitant use of phentermine with methyldopa or reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.

Use caution in combining phentermine with antidiabetic agents. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis.^[41] A pharmacodynamic interaction with antidiabetic agents may occur. Diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.

Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics.^[42] Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.

Concurrent use of phentermine and phenothiazines may antagonize the anorectic effects of phentermine. In addition, psychostimulants can aggravate psychotic states.^[43]

Although not studied, the concomitant use of ethanol and phentermine may result in an adverse reaction and should be avoided.^[34]

Phentermine, like other sympathomimetics, is contraindicated in selected patients with thyroid disease;^[34] caution should be used if coadministering thyroid hormones with phentermine.

Atomoxetine has been reported to increase blood pressure and heart rate, probably via inhibition of norepinephrine reuptake.^[44] Due to an additive pharmacodynamic effect, phentermine and atomoxetine should be used together cautiously, particular in patients with a history of cardiac disease. Consider monitoring heart rate and blood pressure at baseline and regularly throughout treatment if these agents must be used together.

Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine or the combination of phentermine; topiramate, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving these weight loss aides with bupropion or bupropion-containing combinations. Other side effects might also occur, such as dizziness, blood pressure changes, or other side effects. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss.

Due to the pharmacology of salmeterol,^[45] caution and close observation should also be used when fluticasone; salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects based on the pharmacology of salmeterol.^[45]

Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution;^[11] use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended^[46][47] Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine.^[48] However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents.^[49] In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented.^{[50][46][47][51]} In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.^[46][47][51]

Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring.^[52] Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended.^[46][47] Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and the antidepressant fluoxetine.^[48] However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents.^[49] In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented.^{[50][46][47][51]} In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.^[46][47][51]

Phentermine

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.^{[11][53][54][55]}

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.^{[11][53][54][55]}

Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.^{[11][53][54][55]}

Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.^{[11][53][54][55]}

Urticaria has been reported in patients receiving phentermine.^{[11][53][54][55]}

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.^{[54][11][53][55]} 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.^{[54][11][53][55]} 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.^[56] 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.^{[11][53][54][55]}

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.^[2]

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.^[2][4]

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.^[2] 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.^[2] 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.^[2][57] In most cases, signs and symptoms abate with discontinuation of either topiramate or valproate.^[2] 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.^[2]

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.^[2] 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.^[58] 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%).^[2] 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.^[2]

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.^[2]

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.^[2] 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.^[2] 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.^[59] Nephrocalcinosis has been observed with topiramate use during postmarketing experience.^[2]

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.^[2][3]

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.^[27][2]

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.^[60] 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.^[2] 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.^[2][60][61] 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.^[2]
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.^[2]

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.^[2]

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.^[2] 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.^[2] 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.^[2]

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.^[2]

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.^[2]

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.^[2]

Phentermine

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.^[20][20] Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.^[20]

Topiramate

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.^[3] 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.^[2][3] Oral clefts develop in the first trimester before many women know that they are pregnant.^[31] 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.^[2][3] 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.^[3]

Phentermine

Phentermine is contraindicated during breastfeeding.^[20] It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.^[22][21]

Topiramate

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.^[3] Data from 5 breastfeeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration.^[2] 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.^[32]

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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