Kyzatrex Drug Information

Important Dosage Information KYZATREX® is not substitutable with other oral testosterone undecanoate products.

Confirmation of Hypogonadism Before Initiation of KYZATREX® Prior to initiating KYZATRE®, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these testosterone concentrations are below the normal range.

Recommended Dosage and Administration Individualize the dosage of KYZATREX® based on the patient's serum testosterone concentration response to the drug. The recommended starting dose is 200 mg orally twice daily, once in the morning and once in the evening. Take KYZATREX® with food.

Dosage Adjustment Check serum testosterone concentrations 7 days after starting treatment or after dosage adjustment, 3 to 5 hours after the morning dose. Adjust the KYZATREX® dose as necessary as shown in Table 1. Thereafter, periodically monitor serum testosterone concentrations.

The minimum recommended dose is 100 mg once daily in the morning. The maximum recommended dose is 400 mg twice daily. For total daily doses greater than 100 mg, administer the same dose in the morning and evening.

Table 1: KYZATREX® Dosage Adjustment Scheme

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KYZATREX® was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males. All patients initially received KYZATREX® 200 mg orally twice daily.

After the dosage titration period, patients continued their optimized dose for the remainder of the duration of the 6-month study. The mean duration of exposure was 168 days (range: 1 to 180 days). Table 2 summarizes adverse reactions reported in ≥2% of patients in this 6-month study.

Table 2: Adverse Reactions in ≥ 2% of Patients Receiving KYZATREX® in STUDY MRS-TU-2019EXT Adverse Reaction N = 155 n (%) Hypertensión Based upon blood pressure cuff measurements 4 One (0.8%) patient who received KYZATREX® experienced an adverse reaction (acne) that lead to premature discontinuation from the study. In a 12-month, open-label study in hypogonadal adult males (N=212) who received KYZATREX® 200 mg once daily to 400 mg twice daily (n=202) the following additional adverse reactions were reported: headache, arthralgia, diarrhea, hemoglobin increased, anxiety, constipation, peripheral edema, and PSA increased. Blood Pressure Increases In Study MRS-TU-2019EXT, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 155 male patients, 135 of whom completed the study.

ABPM was conducted at 3 distinct 24-hour time periods: at baseline and following approximately 4 months and 6 months of treatment with KYZATREX®. A total of 151 patients had acceptable 24-hour ABPM recordings at both time periods. Ambulatory (24-hour) blood pressure Changes from Baseline for study MRS- TU-2019EXT are presented in Table 3 with 95% confidence intervals.

No significant difference was observed between the 4-month and 6-month Changes from Baseline Table 3: A history of antihypertensive treatment and diabetes mellitus at baseline were significant factors related to ambulatory SBP increases. Table 4 presents the Least Squares Mean estimates of Change from Baseline, with 95% CI’s, for sub-populations of subjects at study start either with or without hypertensive treatment or with or without diabetes mellitus. A total of 5 of 155 patients (3.2%) on KYZATREX® in Study MRS-TU-2019EXT began taking new antihypertensive medications after study start.

No patient had a dose increase in their antihypertensive medication by the end of treatment. Of the 155 patients in Study MRS-TU-2019EXT who used KYZATREX®, 4 patients (2.6%) were reported to have an adverse reaction of hypertension. Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors.

The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months.

Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy. Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.

The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596). For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 ).

Changes in heart rate were similar between patients with or without hypertension or diabetes. Changes in heart rate with treatment were most prominent in the evening, 12 to 17 hours after the morning dose. Increases in Hemoglobin Increases in hemoglobin were reported in 7 out of 155 patients (4.5%) in Study MRS-TU2019EXT.

None of these increases led to premature discontinuation of KYZATREX®. Hematocrit was not assessed in this study. Headaches Headaches were reported in 3 of 155 patients (1.9%) receiving KYZATREX® in Study MRSTU-2019EXT.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Disorders: myocardial infarction, stroke Vascular Disorders: Venous thromboembolism

Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and therefore necessitate a decrease in the dose of anti-diabetic medication.

Oral Vitamin K Antagonist Anticoagulants Changes in anticoagulant activity may be seen with androgens; therefore, more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy.

Corticosteroids

The concurrent use of testosterone with corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal, or hepatic disease.

Medications that May Also Increase Blood Pressure

Some prescription medications and nonprescription analgesic and cold medications contain drugs known to increase blood pressure. Concomitant administration of these medications with KYZATREX® may lead to additional increases in blood pressure.

Pregnancy - Risk Summary KYZATREX® is contraindicated in pregnant women and not indicated for use in females. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies (see Data ) and its mechanism of action. Exposure of a female fetus to androgens may result in varying degrees of virilization.

In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies do not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep, and rhesus monkeys, pregnant animals received intramuscular injections of testosterone during the period of organogenesis.

Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased anogenital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen.

Increased pituitary weight was seen in both sexes. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

Pediatric Use The safety and efficacy of KYZATREX® in pediatric patients less than 18 years old have not been established. KYZATREX® is not recommended for use in patients less than 18 years of age because of the potential for acceleration of bone age and premature closure of epiphyses.

KYZATREX® is contraindicated in: Patients with carcinoma of the breast or known or suspected carcinoma of the prostate. Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman.

Patients with known hypersensitivity to KYZATREX® or any of its ingredients. Carcinoma of the breast or known or suspected carcinoma of the prostate Women who are pregnant. Testosterone may cause fetal harm Hypersensitivity to KYZATREX® or any of its ingredients

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage consists of discontinuation of KYZATREX® and appropriate symptomatic and supportive care.