SIDE EFFECTS

Clinical Studies

In formal clinical trials of 1509 healthy adult patients, symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus occurred in 3 patients (approximately 0.2%).

As would be expected with a drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.

In controlled studies comparing SYNAREL (400 µg/day) and danazol (600 or 800 mg/day), adverse reactions most frequently reported and thought to be drug-related are shown in the figure below:

ADVERSE EVENTS DURING 6 MONTHS TREATMENT WITH SYNAREL® 400 µg/day vs DANAZOL 600 OR 800 mg/day

In addition, less than 1% of patients experienced paresthesia, palpitations, chloasma, maculopapular rash, eye pain, asthenia, lactation, breast engorgement, and arthralgia.

Changes in Bone Density

After six months of treatment with SYNAREL, vertebral trabecular bone density and total vertebral bone mass, measured by quantitative computed tomography (QCT), decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment levels. There was partial recovery of bone density in the post-treatment period; the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment.

After six months treatment with SYNAREL, bone mass as measured by dual x-ray bone densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by DEXA six months after completion of treatment, was 1.4% below pretreatment. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of SYNAREL for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Changes in Laboratory Values During Treatment

Plasma enzymes. During clinical trials with SYNAREL, regular laboratory monitoring revealed that SGOT and SGPT levels were more than twice the upper limit of normal in only one patient each. There was no other clinical or laboratory evidence of abnormal liver function and levels returned to normal in both patients after treatment was stopped.

Lipids. At enrollment, 9% of the patients in the group taking SYNAREL 400 µg/day and 2% of the patients in the danazol group had total cholesterol values above 250 mg/dL. These patients also had cholesterol values above 250 mg/dL at the end of treatment.

Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in the group treated with SYNAREL and 18% in the danazol group, had post-treatment values above 250 mg/dL.

The mean (± SEM) pretreatment values for total cholesterol from all patients were 191.8 (4.3) mg/dL in the group treated with SYNAREL and 193.1 (4.6) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 204.5 (4.8) mg/dL in the group treated with SYNAREL and 207.7 (5.1) mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p < 0.05) in both groups.

Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients who received SYNAREL and in 7% of the patients who received danazol.

At the end of treatment, no patients receiving SYNAREL had abnormally low HDL cholesterol fractions (less than 30 mg/dL) compared with 43% of patients receiving danazol. None of the patients receiving SYNAREL had abnormally high LDL cholesterol fractions (greater than 190 mg/dL) compared with 15% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving SYNAREL, but there was approximately a 2-fold increase in the LDL/HDL ratio in patients receiving danazol.

Other changes. In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Treatment with SYNAREL was associated with elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium and WBC counts. Danazol therapy was associated with an increase of hematocrit and WBC.

Post-Marketing

Pituitary apoplexy: During post-marketing surveillance, rare 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 first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Cardiovascular adverse events: Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.

Read the entire FDA prescribing information for Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for Endometriosis) »