Phentermine And Topiramate Extended-Release

5 WARNINGS AND PRECAUTIONS • Embryo-Fetal Toxicity: Can cause fetal harm. Inpatients who can become pregnant, a negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules and monthly during therapy; advise use of effective contraception. Phentermine and topiramate extended-release capsules are available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS) ( 5.1 ). • Suicidal Behavior and Ideation : Monitor for depression or suicidal thoughts. Discontinue phentermine and topiramate extended-release capsules if symptoms develop (5.2). • Risk of Ophthalmologic Adverse Reactions : Acute myopia and secondary angle closure glaucoma have been reported. Immediately discontinue phentermine and topiramate extended-release capsules if symptoms develop. Consider phentermine and topiramate extended-release capsules discontinuation if visual field defects occur. (5.3). • Mood and Sleep Disorders : Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms (5.4). • Cognitive Impairment: May cause disturbances in attention or memory, or speech/language problems. Caution patients about operating automobiles or hazardous machinery when starting treatment (5.5). • Slowing of Linear Growth : Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected (5.6). • Metabolic Acidosis: Measure electrolytes before and during treatment. If persistent metabolic acidosis develops, reduce dosage or discontinue phentermine and topiramate extended-release capsules (5.7). • Decrease in Renal Function: Measure creatinine before and during treatment. For persistent creatinine elevations, reduce dosage or discontinue phentermine and topiramate extended-release capsules (5.8). • Serious Skin Reactions : Phentermine and topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related (5.13). 5.1 Embryo-Fetal Toxicity Phentermine and topiramate extended-release capsules can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. A negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules treatment in patients who can become pregnant and monthly during phentermine and topiramate extended-release capsules therapy. Advise patients who can become pregnant of the potential risk to a fetus and to use effective contraception during phentermine and topiramate extended-release capsules therapy [see Use in Specific Populations ( 8.1 , 8.3 )] . Phentermine and Topiramate Extended-Release Capsules Risk Evaluation and Mitigation Strategy (REMS) Because of the teratogenic risk associated with phentermine and topiramate extended-release capsules therapy, phentermine and topiramate extended-release capsules are available through a limited program under the REMS. Under the phentermine and topiramate extended-release capsules REMS, only certified pharmacies may distribute phentermine and topiramate extended-release capsules. Further information is available at www.PhenTopREMS.com or by telephone at 1‐800‐269‐6816. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies (monotherapy and adjunctive therapy, median treatment duration 12 weeks) of 11 different AEDs across several indications showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. The estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in AED-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about AED effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age in the clinical trials analyzed. Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue phentermine and topiramate extended-release capsules in patients who experience suicidal thoughts or behaviors [see Warnings and Precautions ( 5.9 )]. Avoid phentermine and topiramate extended-release capsules in patients with a history of suicidal attempts or active suicidal ideation. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 5.3 Risk of Ophthalmological Adverse Reactions Acute Myopia and Secondary Angle Closure Glaucoma A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of phentermine and topiramate extended-release capsules as rapidly as possible in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision. Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing phentermine and topiramate extended-release capsules. 5.4 Mood and Sleep Disorders Phentermine and topiramate extended-release capsules can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 )] . Consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules if clinically significant or persistent symptoms occur. Discontinue phentermine and topiramate extended-release capsules if patients have symptoms of suicidal ideation or behavior [see Warnings and Precautions ( 5.2 )]. 5.5 Cognitive Impairment Phentermine and topiramate extended-release capsules can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of phentermine and topiramate extended-release capsules may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties [see Adverse Reactions ( 6.1 )] . The concomitant use of alcohol or central nervous system (CNS) depressant drugs with phentermine and topiramate extended-release capsules may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination, and somnolence. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain phentermine and topiramate extended-release capsules therapy does not affect them adversely. Caution patients against excessive alcohol intake while receiving phentermine and topiramate extended-release capsules. If cognitive dysfunction persists, consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 )]. 5.6 Slowing of Linear Growth Phentermine and topiramate extended-release capsules are associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients. Monitor height velocity in pediatric patients treated with phentermine and topiramate extended-release capsules. Consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules if pediatric patients are not growing or gaining height as expected [see Warnings and Precautions ( 5.9 )]. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 5.7 Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 )]. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, or ketogenic diet) may be additive to the bicarbonate lowering effects of phentermine and topiramate extended-release. Concomitant use of phentermine and topiramate extended-release capsules and a carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions ( 5.10 )] . Avoid use of phentermine and topiramate extended-release capsules with other carbonic anhydrase inhibitors. If concomitant use of phentermine and topiramate extended-release capsules with another carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance or worsening of metabolic acidosis. Measure electrolytes including serum bicarbonate prior to starting phentermine and topiramate extended-release capsules and during phentermine and topiramate extended-release treatment. In phentermine and topiramate extended-release clinical trials, the peak reduction in serum bicarbonate typically occurred within 4 weeks of titration to the assigned dose, and in most patients, there was a correction of bicarbonate by week 56, without any dosage reduction. However, if persistent metabolic acidosis develops while taking phentermine and topiramate extended-release capsules, reduce the dosage or discontinue phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 )]. 5.8 Decrease in Renal Function Phentermine and topiramate extended-release capsules can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate). In clinical trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The changes in serum creatinine (and measured GFR) with short-term (4-weeks) phentermine and topiramate extended-release treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known. Measure serum creatinine prior to starting phentermine and topiramate extended-release capsules and during phentermine and topiramate extended-release capsules treatment. If persistent elevations in creatinine occur, reduce the dosage or discontinue phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 ), Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.2 )]. 5.9 Risk of Seizures with Abrupt Withdrawal of Phentermine and Topiramate Extended-Release Capsules Abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of phentermine and topiramate extended-release capsules is medically required, appropriate monitoring is recommended. Patients discontinuing phentermine and topiramate extended-release capsules 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see Dosage and Administration ( 2.3 ) and Drug Abuse and Dependence ( 9.3 )] 5.10 Kidney Stones Phentermine and topiramate extended-release capsules have been associated with kidney stone formation [see Adverse Reactions ( 6.1 )] . Topiramate inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Patients on a ketogenic diet may be at increased risk for kidney stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year, active-controlled study. Increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. Avoid the use of phentermine and topiramate extended-release capsules with other drugs that inhibit carbonic anhydrase [see Drug Interactions ( 7 )] . Advise patients to increase fluid intake (to increase urinary output), which may decrease the concentration of substances involved in kidney stone formation. 5.11 Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients and caregivers to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Patients on concomitant medications that predispose them to heat-related disorders may be at increased risk. 5.12 Hypokalemia Phentermine and topiramate extended-release capsules can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when phentermine and topiramate extended-release capsules are used in conjunction with non-potassium sparing diuretics this may further potentiate potassium-wasting. Measure potassium before and during treatment with phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )]. 5.13 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Phentermine and topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.14 Allergic Reaction s Due to Inactive Ingredient FD&C Yellow No. 5 Phentermine and topiramate extended-release capsules, 11.25 mg/69 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.