Cardiovascular
In the current Zoloft labeling, it is noted that analysis of ECG data from 774 patients receiving sertraline in clinical trials revealed no pattern of significant ECG abnormalities.
In this database, cardiovascular adverse experiences were not important causes of discontinuation from treatment and were not among the common, drug related adverse events. A slight decrease in mean heart rate was observed, as noted above. No serious adverse events involved the cardiovascular system. One Japanese subject withdrew for palpitations; two subjects withdrew for hypertension but both had previous histories of high blood pressure, and one subject withdrew for tachycardia.
These data do not provide evidence that sertraline treatment of panic disorder patients presents any unique cardiovascular risk.
Gastrointestinal
Nausea, diarrhea and dyspepsia are recognized adverse reactions to sertraline treatment, as described in the current Zoloft labeling. In these clinical trials, no serious adverse events involved the gastrointestinal system. There were a total of 27 adverse gastrointestinal events associated with premature disoncontinuation in sertraline treated patients. Among these, the most common were nausea, diarrhea, and dyspepsia. Thus there did not appear to be a unique pattern of adverse drug reactions for panic disorder patients in this body system.
Hemic and Lymphatic
Setraline treatment has been associated with abnormal platelet function as manifested by abnormal bleeding and purpura; otherwise sertraline is not believed to exert much effect on this body system. No serious adverse events involving the hemic and lymphatic system were observed. One sertraline subject (#197) discontinued for vaginal bleeding, which could have been a manifestation of platelet dysfunction. There was no evidence for a risk specific to panic disorder patients involving this organ system.
Metabolic and Endocrine
Sertraline treatment has been associated with SIADH and with weight loss. In these trials sertraline treatment produced a slight decrease in mean weight. There was one serious adverse endocrine event: subject #047 was hospitalized for diabetes mellitus and was treated with insulin. This seems unlikely to be drug related, however. A slight but statistically significant increase in mean serum cholesterol was observed in sertraline patients, with a net difference in change from baseline of 11 mg/dl for sertraline versus placebo. Dr. Knudsen observed a similar finding in his review of the sertraline clinical trials for obsessive compulsive disorder. As Dr. Knudsen noted in his review, increase in cardiovascular mortality is a continuous function of serum cholesterol levels. For comparison, the mean decrease in serum cholesterol observed in hyperchloesterolemic patients receiving the cholesterol lowering drug lovastatin appears to be roughly 20%. A drug which increases mean cholesterol levels could, conceivably, convey added cardiovascular risk.
Musculoskeletal
Serious adverse events in this database for the musculoskeletal system resulted from motor vehicle accidents. Sertraline patient #176 sustained multiple fractures in a motorcycle accident; the patient had been drinking at the time. Sertraline patient #602 sustained a leg fracture in a motorcycle accident, and sertraline patient #1071 fractured a femur and his wrist in a motor vehicle accident (it was not specified if the patient was driving). In addition, placebo patient #404 was hospitalized for observation after head trauma in a motor vehicle accident. Although it is somewhat unusual to observe this many injuries from auto accidents in a relatively small clinical trial development program, I would not conclude that sertraline us increases the risk of motor vehicle accidents, particularly since one accident occurred in the placebo group, and clinical study data shows no adverse psychomotor effects from sertraline treatment. Otherwise, there were no important adverse experiences involving the musculoskeletal system.
Nervous
Nervous system adverse experiences associated with sertraline treatment include agitation, insomnia, tremor, dizziness, somnolence, fatigue, headache, and activation of mania, all described in the current Zoloft package insert. In this data set, there was one seizure in a placebo patient and none in sertraline patients. No suicidal ideation was reported in sertraline treated patients. There was one patient (#398) who experienced what was described as an aggressive reaction to the first sertraline dose, and discontinued from the study. Serious adverse events in sertraline treated patients involving the nervous system included labrynthitis with discovery of a cerebral aneurysm after a neurological workup (patient #151); and syncope, twitching and tremulousness which after in patient evaluation were deemed to be manifestations of panic attacks (patient #612). One patient whose treatment remained blinded (#2280040) was withdrawn and hospitalized for severe anxiety. I do not believe that sertraline was causally related to any of these serious events. One patient (#176) was discontinued from sertraline treatment because of agitation, and hallucinations which resolved after discontinuation.
Altogether, 51 of the 61 sertraline patients who discontinued prematurely had associated adverse psychiatric events; for the most part, these events were similar to those already described in association with sertraline as noted above. There were no instances of treatment emergent mania among sertraline patients. Paresthesia, dizziness and headache were the most common neurological events associated with premature withdrawal.
As noted above under the heading Literature, Pfizer furnished copies of two reports describing a total of three cases of treatment emergent panic attacks associated with sertraline therapy of other disorders. One of these patients had concurrent suicidal ideation. It is possible that certain individuals may be susceptible to such reactions to sertraline treatment; however, the weight of evidence presented in this supplement supports an anti-panic effect of sertraline rather than a panic-provoking effect. On balance, these data do not suggest a unique pattern of nervous system side effects for panic disorder patients receiving sertraline.
Respiratory
Sertraline is not noted for effects on the respiratory tract. In this database, hyperventilation and upper respiratory tract infection accounted for one premature discontinuation each; no serious adverse events involved the respiratory system. Sertraline treatment of panic disorder does not appear to involve any particular risk to the respiratory system.
Dermatologic
The Division has recently requested Pfizer to amend the Zoloft labeling to describe certain severe cutaneous adverse drug reactions associated with sertraline, such as toxic epidermal necrolysis. No serious cutaneous adverse experiences were observed in these clinical trials. Two sertraline patients discontinued with urticaria. Sertraline does not seem to present unique dermatologic risks for panic disorder patients.
Special Senses
No serious adverse experiences involved the special senses, and no pattern of adverse experiences or adverse dropouts involving special senses was found which might signal a risk with use of sertraline.
Genitourinary
Sertraline patient #508 had surgery for bladder carcinoma; this was the only serious adverse event involving the genitourinary system. Ejaculation failure was a common adverse event and one of the frequent causes of premature discontinuation; however, this has been noted previously in association with sertraline use and is not unique to panic disorder patients.
A slight but statistically significant effect on serum uric acid concentrations was observed, with sertraline producing a slight decrease. Sertraline is known to have a weak uricosuric effect (please refer to the current package insert).