Immediate-Onset Systemic Allergic Reactions (See Boxed Warnings)
In the clinical trial of patients with advanced, symptomatic prostate cancer, 3 of 81 (3.7%) patients experienced an immediate-onset systemic allergic reaction within minutes of receiving Plenaxis®. The allergic reactions were urticaria (Day 15), urticaria and pruritis (Day 29), and hypotension and syncope (Day 141). Patients should be monitored for at least 30 minutes after each injection of Plenaxis®. In the event of an allergic reaction associated with hypotension and/or syncope, appropriate supportive measures such as leg elevation, oxygen, IV fluids, antihistamines, corticosteroids, and epinephrine (alone or in combination) should be employed.
From all the prostate cancer clinical trials with Plenaxis® (mostly in men without advanced, symptomatic disease), immediate-onset systemic allergic reactions (occurring within 30 minutes of dosing), were observed in 1.1% (15/1397) of patients dosed with Plenaxis®. In 14/15 patients who experienced an allergic reaction, each developed symptoms within 8 minutes of injection. The cumulative risk of such a reaction increased with duration of treatment. The cumulative rates (and 95% confidence intervals) on Days 56, 141, 365 and 676 were 0.51%, (0.13%, 0.88%) 0.80% (0.30%, 1.29%), 1.24% (0.43%, 2.04%) and 2.91% (0.87, 4.95%), respectively. Seven patients experienced hypotension or syncope as part of their allergic reaction, representing 0.5% of all patients. The cumulative rates (and 95% confidence intervals) for these types of reactions on Days 56, 141, 365, and 617 after the initial dose were 0.22% (0.0%, 0.46%), 0.32% (0.0%, 0.64%), 0.61% (0.0%, 1.24%) and 1.67% (0.07, 3.28%), respectively.
DECREASE IN EFFECTIVENESS WITH CONTINUED DOSING
A decrease in overall effectiveness with increased duration of treatment, as measured by failure to maintain suppression of serum testosterone below 50 ng/dL, was noted (see Clinical Pharmacology, Pharmacodynamics). Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 after the initial dose and every 8 weeks thereafter.
PROLONGATION OF THE QT INTERVAL
Because Plenaxis® may prolong the QT interval (see Clinical Pharmacology, Pharmacodynamics), physicians should carefully consider whether the risks of Plenaxis® outweigh the benefits in patients with baseline QTc values >450 msec (e.g. congenital QT prolongation) and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications.
Decreased effectiveness in patients >225 pounds: The decrease in overall effectiveness of Plenaxis® with increased duration of treatment is greater in patients who weigh more than 225 pounds. Strict monitoring of serum testosterone in these patients is warranted.
Monitoring of liver function: Clinically meaningful transaminase elevations were observed in some patients who received Plenaxis® or comparator drugs. Serum transaminase levels should be obtained before starting treatment with Plenaxis® and periodically during treatment (see Adverse Reactions).
Decrease in bone mineral density: Extended treatment with GnRH antagonists and LHRH agonists may result in a decrease in bone mineral density.
No formal drug/drug interaction studies with Plenaxis® were performed. Cytochrome P-450 is not known to be involved in the metabolism of Plenaxis®. Plenaxis® is highly bound to plasma proteins (96 to 99%).
Response to Plenaxis® should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see WARNINGS). Serum transaminase levels should be obtained before starting treatment with Plenaxis® and periodically during treatment. Periodic measurement of serum PSA levels may also be considered.
Prostate cancer occurs primarily in an older patient population. Clinical studies with Plenaxis® have been conducted primarily in patients >/= 65 years of age. No difference in the safety profile, when examined as a function of age, was apparent.
The safety and effectiveness of Plenaxis® in pediatric patients have not been studied. Plenaxis® is not indicated for use in pediatric patients.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Plenaxis® was not carcinogenic to mice or rats when administered as a subcutaneous depot every 28 days for 2 years at doses up to 300 mg/kg in mice and 100 mg/kg in rats. Systemic drug exposures, as measured by mean Cmax, were approximately 210-278-fold for mice and 21-32-fold for rats the human exposure following subcutaneous depot administration of 100 mg.
Plenaxis® was not mutagenic in the in vitro bacterial Ames assay or forward mutation assay in mouse lymphoma, or clastogenic in the in vivo mouse micronucleus assay.
No effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous Plenaxis®, a dose 0.114-fold the human therapeutic dose of 100 mg based on body surface area. Mating and fertility were significantly decreased at doses of 3 and 10 mg/kg (0.34-fold and 1.135-fold, respectively, the human therapeutic dose of 100 mg based on body surface area), but the effects were reversible.
PREGNANCY CATEGORY X (EE CONTRAINDICATIONS)
Embryolethality occurred in pregnant rats administered a single subcutaneous dose of Plenaxis® up to 3 mg/kg (0.228-fold the human therapeutic dose of 100 mg based on body surface area). In rabbits a dose-related increase in fetal resorptions and reduced viability was observed at doses up to 30 mg/kg (6.81-fold the human therapeutic dose of 100 mg based on body surface area). No teratogenic effects were observed in rats or rabbits up to doses of 3 mg/kg or 30 mg/kg, respectively. A no-observable-adverse-effect-level (NOAEL) dose was 0.3 mg/kg (approximately 0.034-fold the human therapeutic dose of 100 mg based on body surface area) in rats and <0.01 mg/kg (<0.0023-fold the human therapeutic dose of 100 mg based on body surface area) in rabbits.
It is not known whether Plenaxis® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Plenaxis® on lactation and/or the breastfed child have not been determined, Plenaxis® should not be used by nursing mothers.