Phentermine - Warnings and Precautions

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) . • Suicidal Behavior and Ideation : Monitor for depression or suicidal thoughts.

Discontinue phentermine and topiramate extended-release capsules if symptoms develop . • 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. . • Mood and Sleep Disorders : Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms . • Cognitive Impairment: May cause disturbances in attention or memory, or speech/language problems.

Caution patients about operating automobiles or hazardous machinery when starting treatment . • Slowing of Linear Growth : Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected . • Metabolic Acidosis: Measure electrolytes before and during treatment.

If persistent metabolic acidosis develops, reduce dosage or discontinue phentermine and topiramate extended-release capsules . • Decrease in Renal Function: Measure creatinine before and during treatment.

For persistent creatinine elevations, reduce dosage or discontinue phentermine and topiramate extended-release capsules . • 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 .

5.1 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.