Pharmacology Update

Paroxetine Controlled Release (Paxil CR)—New Dosage Form for Panic Disorder

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Recently the FDA approved paroxetine controlled-release (CR) tablets for the treatment of panic disorder. It joins the immediate-release (IR) form of paroxetine and sertraline as the selective serotonin reuptake inhibitors (SSRIs) with this indication.

Indications

Paroxetine CR tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. It is also indicated for the treatment of major depression, obsessive compulsive disorder, general anxiety disorder, social anxiety disorder, and post-traumatic stress disorder.1

Dosage

The recommended starting dose for panic disorder is 12.5 mg per day. The dose may be increased at 12.5 mg increments no sooner than 1 week after initiating therapy. The dose range is 12.5 mg to 75 mg per day. In clinical trials, the mean dose was 50 mg per day. The tablet should not be chewed or crushed and may be taken without regard to meals.1

CR paroxetine is available as 12.5-mg, 25-mg, and 37.5-mg tablets.

Potential Advantages

The incidence of nausea or vomiting may be initially less with the CR formulation compared to the immediate release (IR) formulation. In a randomized, placebo-controlled, 3-day study (n = 120), the proportion of patients reporting nausea and/or vomiting for CR 30 mg, IR 30 mg, and placebo were 40%, 59%, and 13%, respectively.2 However, whether this is maintained over time is not known as patients tend to adapt to this side effect with continued use.1 Paroxetine is the only SSRI currently approved for all 5 anxiety disorders. It is generally well tolerated and has a low potential for causing jitterness.3 SSRIs have generally been considered the treatment of choice in patients who never had pharmacotherapy.4,5 While this appears to be a class effect, they do differ in side effects and potential for drug interactions.

Potential Disadvantages

Paroxetine inhibits cytochrome P450 isoenzyme 2D6 and drugs that are metabolized by this isoenzyme must be co-administered with caution. Citalopram and sertraline are options if interaction with 2D9 is problematic.

Sexual dysfunction is a side effect of paroxetine. The most common manefestations are ejaculatory disturbance (27% vs 3% for placebo), impotence (10% vs 1%), decreased libido (8% vs 2%), and orgasmic disturbance (7% vs 1%).1 Based on a survey questionnaire of 1022 antidepressant patients, the incidence of reported sexual dysfunction was 71% (147/208) for paroxetine. This was higher than that reported for fluoxetine 58% (161/279) and sertraline 63% (100/159).6 Paroxetine is more sedating than sertraline or fluoxetine. Withdrawal symptoms (eg, dizziness, light-headedness, nausea, vomiting, flu-like symptoms, sensory, and sleep disturbance) upon abrupt or brief discontinuation appeared to be more likely with paroxetine than fluoxetine.7,8 Gradual tapering of the dose is recommended.1

Comments

CR paroxetine is formulated in a degradable polymeric matrix (Geometrix). It is designed to control the release of the drug over a 4-5 hour period. An enteric coat also delays the release until the table has entered the small intestine. The peak plasma level is achieved in 6-10 hours compared to about 5 hours for the IR form. The mean peak level is about one half of that of the IR form (30 ng/mL to 60 ng/mL). The elimination half-life is not altered by the delivery system. It is not clear if the CR formulation significantly alters the pharmacodynamics of paroxetine. The effectiveness in treating panic disorder was shown in 2 out of 3 10-week, placebo-controlled studies with the CR formulation.1 The end points were proportion of patients free of full panic attacks, change from baseline in the median number of full attacks, and change from baseline in the median Clinical Global Impression Severity Score. Long-term maintenance (3 months) efficacy has been shown only with the IR formulation.1

Clinical Implications

It is estimated that 1.7% of the US adult population have panic disorder in any given year.4 It primarily affects women and the incidence declines with age with the highest between 18-29 years. It tends to closely mimic medical disorders and often results in high use of health care resources and diagnostic procedures.4 Panic disorder is characterized by a discrete period of intense fear or discomfort and 4 or more of the following symptoms that develop abruptly and reach a climax within 10 minutes: palpitations, sweating, trembling or shaking, sensation of shortness of breath or smothering, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling of dizzy, unsteady, lightheaded, or faint, derealization or depersonalization, fear of losing control, fear of dying, paresthesias, or chills or hot flashes.9 Pharmacologic management includes antidepressants and benzodiazepines. SSRIs are generally considered the initial treatment of choice. The specific agent should be tailored to the patient’s panic symptom profile, comorbid conditions, and potential drug interactions. The regimen may need to be adjusted due to the patient’s tolerance to the drug. CR paroxetine offers another formulation of an effective SSRI for the treatment of panic disorder. It is not clear if the CR formulation offers any significant advantage over the IR counterpart.

References

1. Paxil CR Product Information. GlaxoSmith Kline. February 2002.

2. Clinical Pharmacology and Biopharmaceutics Review 2/29/99. http://www.fda.gov/cder/approval/index.htm.

3. Toni C, et al. Pharmacopsychiatry. 2000;33(4):121-331.

4. Roy-Byrne P, et al. J Am Board Fam Prac. 1998;11(4): 282-290.

5. Bakker A, et al. Int Clin Psychopharmacol. 2000; 15(suppl 2):25-30.

6. Montejo AL, et al. J Clin Psychiatry. 2001;62 (suppl 3):10-21.

7. Hindmarch I, et al. Int Clin Psychopharmacol. 2000; 15(6):305-318.

8. Price JS, et al. Br J Clin Pharmacol. 1996;42(6): 757-763.

9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. DSM-IV. Washington, DC: American Psychiatric Press; 1994.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.