Jane S. Ricciuti, RPh, MS

Disclosures

January 29, 2004

In This Article

Urologic Agents

Cialis
(tadalafil) Tablets

Manufacturer: Lilly ICOS LLC

Drug Approval Classification: Original New Drug Application (Approval Date: 11/21/03)

Indication: Cialis (tadalafil) is indicated for the treatment of erectile dysfunction (ED).

Dosing: The recommended dose of tadalafil is 10 mg prior to sexual activity. The maximum recommended dose is 20 mg once a day at 5-mg increments. The effects of tadalafil may last for up to 36 hours.

In patients with severe renal insufficiency (CrCl < 30 mL/min), the maximum recommended dose is 5 mg. In patients with moderate hepatic impairment, the recommended dose is 10 mg.

Tadalafil may be taken with or without food.

Tadalafil is available in 5-, 10-, and 20-mg tablets.

Clinical Summary: Tadalafil is an oral selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Tadalafil has been studied in 22 clinical trials with over 4000 patients and has demonstrated an effect in improving erectile function in men with ED. Primary outcome measures included the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP).

The 2 pivotal US safety and efficacy trials included a total of 402 men with ED, with a mean age of 59 years (range, 27-87 years). The population included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple comorbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease.

Tadalafil 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables. The treatment effect of tadalafil did not diminish over time.

Contraindications: Tadalafil is contraindicated in those patients who are using the following medications:

  • Nitrates

  • Alpha blockers (other than 0.4 mg once-daily tamsulosin)

Adverse Effects: In clinical trials, the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared with 1.4% in placebo-treated patients. Most common adverse effects were headache (11% to 15%), dyspepsia (4% to 10%), and back pain (3% to 6%).

Back pain, a diffuse bilateral lower lumbar pain, occurred at 12-24 hours after dosing and generally resolved within 48 hours without medical treatment.

Pharmacokinetics: Steady-state plasma concentrations are attained within 5 days of once-daily dosing. Tadalafil is eliminated predominantly by hepatic metabolism, mainly by cytochrome P450 3A4 (CYP3A4). The concomitant use of potent CYP3A4 inhibitors such as ritonavir or ketoconazole resulted in significant increases in tadalafil AUC values.

The maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours); the mean apparent volume of distribution following oral administration is approximately 63 L. The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects.

Drug Interactions

Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure:

  • Ketoconazole

  • HIV Protease inhibitor (ritonavir)

Cytochrome P450 inducers can decrease tadalafil exposure:

  • Rifampin

  • Gastrointestinal drugs

  • H2 antagonists

  • Antacids

Substantial consumption of alcohol (eg, 5 units or greater) in combination with Cialis can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

Cialis (tadalafil) Tablets Labeling

Plenaxis
(abarelix) Injectable Suspension

Manufacturer: Praecis Pharmaceuticals

Drug Approval Classification: Original New Drug Application (Approval Date: 11/25/03)

Indication: Plenaxis (abarelix) is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have 1 or more of the following:

  • risk of neurologic compromise due to metastases,

  • ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or

  • severe bone pain from skeletal metastases persisting on narcotic analgesia.

Dosing: The recommended dose of abarelix is 100 mg administered intramuscularly to the buttock on day 1, 15, 29 (week 4) and every 4 weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to abarelix administration, beginning on day 29 and every 8 weeks thereafter.

Complete reconstitution instructions are provided in the package labeling.

Clinical Summary: Abarelix labeling contains a black box warning indicating that, in order to prescribe abarelix, physicians must be enrolled in the Plenaxis PLUS Program (Plenaxis User Safety Program), based on their attestation to qualifications and acceptance of prescribing responsibilities. The boxed warning contains the following information:

  • Warning:

    • Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have occurred after administration of Plenaxis. These immediate-onset reactions have been reported to occur following any administration of Plenaxis, including after the initial dose. The cumulative risk of such a reaction increases with the duration of treatment. Following each injection of Plenaxis, patients should be observed for at least 30 minutes in the office and, in the event of an allergic reaction, managed appropriately.

    • Only physicians who have enrolled in the Plenaxis™ PLUS Program (Plenaxis User Safety Program), based on their attestation of qualifications and acceptance of prescribing responsibilities, may prescribe Plenaxis.

    • Plenaxis is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia.

    • The effectiveness of Plenaxis in suppressing serum testosterone to castrate levels decreases with continued dosing in some patients. Effectiveness beyond 12 months has not been established. Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on day 29 and every 8 weeks thereafter.

Abarelix inhibits gonadotropin and related androgen production by directly and competitively blocking GnRH receptors in the pituitary.

Two randomized, open-label, active-comparator trials evaluated the effectiveness of abarelix. Patients were randomized in a 2:1 ratio to abarelix 100 mg intramuscularly (IM) vs LHRH agonist (Study 1) or to abarelix vs LHRH agonist + nonsteroidal antiandrogen (Study 2). Plenaxis was administered IM on days 1, 15, and 29 (week 4), then every 4 weeks thereafter for at least 6 months (24 weeks). After completing 6 months of treatment, patients could continue randomized treatment for an additional 6 months.

In both studies combined, 100% (348/348) of abarelix patients and 16% (28/172) of comparator patients avoided a testosterone surge.

Successful response was defined as attainment of medical castration on day 29 and maintenance through day 85. In Study 1, 92% of abarelix patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of abarelix patients and 95% of LHRH agonist + nonsteroidal antiandrogen patients responded.

Adverse Effects: Periodic electrocardiograms were performed in one of the abarelix studies. Both therapies, abarelix and comparator, prolonged the mean Fridericia-corrected QT interval by > 10 msec from baseline. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.

The most common side effects seen in the clinical trial were hot flashes, sleep disturbances, pain, including back pain, breast enlargement or pain, and constipation.

Pharmacokinetics: Abarelix mean Cmax is 43.4 ± 32.3 ng/mL; Tmax is 3.0 ± 2.9 days; AUC of 500 ± 96 ng*days/mL; and half-life of 13.2 ± 3.2 days.

There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.

Plenaxis (abarelix) Injectable Suspension Labeling

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