FORTESTA (Page 5 of 7)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, implant-induced cervical-uterine tumors metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.
Mutagenesis
Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.
Impairment of Fertility
The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog, and non-human primates, which was reversible on cessation of the treatment.
14 CLINICAL STUDIES
14.1 Clinical Study in Hypogonadal Males
FORTESTA was evaluated in a multicenter, 90-day open-label, non-comparative trial of 149 hypogonadal males with body mass index (BMI) ≥ 22 kg/m2 and < 35 kg/m2 and 18 to 75 years of age (mean age 54.5 years). The patients were screened for a single serum total testosterone concentration < 250 ng/dL, or 2 consecutive serum total testosterone concentrations < 300 ng/dL. Patients were caucasian (80.5%), black (10.1%), Hispanic (7.4%), and other (2.0%).
FORTESTA was applied once each morning to the thighs at a starting dose of 40 mg of testosterone (4 pump actuations) per day. The dose was adjusted between a minimum of 10 mg and a maximum of 70 mg testosterone on the basis of total serum testosterone concentration obtained 2 hours post FORTESTA application on Days 14, 35, and 60 (± 3 days).
The primary endpoint was the percentage of patients with Cavg within the normal range (greater than or equal to 300 ng/dL and less than or equal to 1140 ng/dL) on Day 90. In patients treated with FORTESTA, 77.5% (100/129) had Cavg within the normal range on Day 90. The secondary endpoint was the percentage of patients with Cmax above 3 pre-determined limits. The percentages of patients with Cmax greater than 1500 ng/dL, and between 1800 and 2499 ng/dL on Day 90 were 5.4% and 1.6%, respectively. No patient had a Cmax greater than or equal to 2500 ng/dL on Day 90.
Dose titrations on Days 14, 35, and 60 resulted in mean (SD) Cavg and Cmax for final doses of 10 mg to 70 mg on Day 90 shown in Table 5.
Table 5: Mean (±SD) Steady-State Testosterone Concentrations (Cavg and Cmax ) by Final Dose on Day 90
| Final Dose | ||||||||
| 10mg(n=1) | 20mg(n=6) | 30mg (n=16) | 40mg(n=30) | 50mg(n=26) | 60mg(n=27) | 70mg(n=23) | ||
| Cavg (ng/dL) | Mean | 196 | 464 | 392 | 444 | 483 | 441 | 415 |
| SD | 205 | 164 | 176 | 156 | 163 | 136 | ||
| Cmax (ng/dL) | Mean | 503 | 971 | 775 | 855 | 964 | 766 | 724 |
| SD | 399 | 278 | 417 | 389 | 292 | 313 | ||
Figure 2 summarizes the pharmacokinetic profiles of total testosterone in patients completing 90 days of FORTESTA treatment administered as 40 mg of testosterone once-daily for the initial 14 days followed by possible titration according to follow-up testosterone measurements.
Figure 2: Mean (±SD) Steady-State Serum Total Testosterone Concentrations on Day 90 (N=129)
Additionally, there were no clinically significant changes from baseline for SHBG (slight decrease), estradiol (slight increase), and ratio of DHT to total testosterone (slight increase) at Day 90.
16 HOW SUPPLIED/STORAGE AND HANDLING
FORTESTA is supplied in 60 g canisters with a metered dose pump that delivers 10 mg of testosterone per complete pump actuation. The metered dose pump is capable of dispensing 120 metered pump actuations. One (1) pump actuation dispenses 0.5 g of gel.
FORTESTA is available in packages of 1, 2, and 3 canisters (NDC 63481-183-16, NDC 63481-183-17, and NDC 63481-183-18, respectively).
Store at controlled room temperature 20o C-25o C (68o F-77o F); excursions permitted to 15o C-30o C (59o F-86o F). [See USP]. Do Not Freeze.
Used FORTESTA canisters should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.
17 PATIENT COUNSELING INFORMATION
See FDA-approved Medication Guide.
Patients should be informed of the following information:
17.1 Use in Men with Known or Suspected Prostate or Breast Cancer
Men with known or suspected prostate or breast cancer should not use FORTESTA [see Contraindications (4) and Warnings and Precautions (5.1)].
17.2 Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure
Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men. Cases of secondary exposure to testosterone in children have been reported.
Physicians should advise patients of the reported signs and symptoms of secondary exposure which may include the following:
- In children; unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior.
- In women; changes in hair distribution, increase in acne, or other signs of testosterone effects.
- The possibility of secondary exposure to FORTESTA should be brought to the attention of a healthcare provider.
- FORTESTA should be promptly discontinued until the cause of virilization is identified.
Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from FORTESTA in men [see Medication Guide]:
- Children and women should avoid contact with unwashed or unclothed application site(s) of men using FORTESTA.
- Patients using FORTESTA should apply the product as directed and strictly adhere to the following:
- Wash hands with soap and water after application.
- Cover the application site(s) with clothing after the gel has dried.
- Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated.
- In the event that unwashed or unclothed skin to which FORTESTA has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration (2.2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].
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