Adverse Reactions In Clinical Trials
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 VANTAS was evaluated in 171 patients with prostate cancer treated for up to 36 months in two clinical trials. The pivotal study (Study 1) consisted of 138 patients, while a separate supportive study (Study 2) consisted of 33 patients.
VANTAS, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first week of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see WARNINGS AND PRECAUTIONS].
In the first 12 months after initial insertion of the implant(s), an implant extruded through the incision site in eight of 171 patients in the clinical trials (see the Recommended Procedure for correct implant placement).
In the pivotal study (Study 1) a detailed evaluation for implant site reactions was conducted. Out of the 138 patients in the study, 19 patients (13.8%) experienced local or insertion site reactions. All these local site reactions were reported as mild in severity. The majority were associated with initial insertion or removal and insertion of a new implant, and began and resolved within the first two weeks following implant insertion. Reactions persisted in 4 (2.8%) patients. An additional 4 (2.8%) patients developed application-site reactions after the first two weeks following insertion.
Local reactions after implant insertion included bruising (7.2% of patients) and pain/soreness/tenderness (3.6% of patients). Other, less frequently reported, reactions included erythema (2.8% of patients) and swelling (0.7% of patients). In this study, two patients had events described as local infections/inflammations, one that resolved after treatment with oral antibiotics and the other without treatment.
Local reactions following insertion of a subsequent implant were comparable to those seen after initial insertion.
The following possibly or probably related systemic adverse events occurred during clinical trials of up to 24 months of treatment with VANTAS, and were reported in ≥ 2% of patients (Table 1).
Table 1: Incidence (%) of Possibly or Probably Related
Systemic Adverse Events Reported by ≥ 2% of Patients Treated with
VANTAS for up to 24 Months
|Body System||Adverse Event||Number (%)|
|Vascular Disorders||Hot flashes*||112 (65.5%)|
|General Disorders||Fatigue||17 (9.9%)|
|Weight increased||4 (2.3%)|
|Skin and Appendage Disorders||Implant site reaction||10 (5.8%)|
|Reproductive System and Breast Disorders||Erectile dysfunction'||6 (3.5%)|
|Testicular atrophy*||9 (5.3%)|
|Psychiatric Disorders||Insomnia||5 (2.9%)|
|Libido decreased*||4 (2.3%)|
|Renal and Urinary Disorders||Renal impairment**||8 (4.7%)|
|Gastrointestinal Disorders||Constipation||6 (3.5%)|
|Nervous System Disorders||Headache||5 (2.9%)|
|* Expected pharmacological
consequences of testosterone suppression.
** 5 of the 8 patients had a single occurrence of mild renal impairment (defined as creatinine clearance ≥ 30 < 60 mL/min), which returned to a normal range by the next visit.
Hot flashes were the most common adverse event reported (65.5% of patients). In terms of severity, 2.3% of patients reported severe hot flashes, 25.4% of patients reported moderate hot flashes and 37.7% reported mild hot flashes. In addition, the following possibly or probably related systemic adverse events were reported by < 2% of patients using VANTAS in clinical studies.
- Blood and Lymphatic System Disorders: Anemia
- Cardiac Disorders: Palpitations, ventricular extrasystoles
- Gastrointestinal Disorders: Abdominal discomfort, nausea
- General Disorders: Feeling cold, lethargy, malaise, edema peripheral, pain, pain exacerbated, weakness, weight decreased
- Hepatobiliary Disorders: Hepatic disorder
- Injury, Poisoning and Procedural Complications: Stent occlusion
- Laboratory Investigations: Aspartate aminotransferase increased, blood glucose increased, blood lactate dehydrogenase increased, blood testosterone increased, creatinine clearance decreased, prostatic acid phosphatase increased
- Metabolism and Nutrition Disorders: Appetite increased, fluid retention, food craving, hypercalcaemia, hypercholesterolemia
- Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, back pain aggravated, bone pain, muscle twitching, myalgia, neck pain, pain in limb
- Nervous System Disorders: Dizziness, tremor
- Psychiatric Disorders: Depression, irritability
- Renal and Urinary Disorders: Calculus renal, dysuria, hematuria aggravated, renal failure aggravated, urinary frequency, urinary frequency aggravated, urinary retention
- Reproductive System and Breast Disorders: Breast pain, breast tenderness, genital pruritus male, gynecomastia aggravated, sexual dysfunction
- Respiratory, Thoracic and Mediastinal Disorders: Dyspnea exertional
- Skin and Subcutaneous Tissue Disorders: Contusion, hypotrichosis, night sweats, pruritus, sweating increased
- Vascular Disorders: Flushing, hematoma
- Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.
The following adverse reactions have been identified during post approval use of VANTAS. 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.
Cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the final dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, opthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
Drug-Induced Liver Injury
Severe liver injury has been reported in association with VANTAS. The toxicity was reversible with the removal of the VANTAS implant.
Nervous System Disorders
Read the Vantas (histrelin acetate) Side Effects Center for a complete guide to possible side effects
No pharmacokinetic-based drug-drug interaction studies were conducted with VANTAS [see CLINICAL PHARMACOLOGY].
Drug-Laboratory Test Interactions
Therapy with histrelin results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after histrelin therapy may be affected.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/10/2014
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