Adverse reactions : תופעות לוואי

6       ADVERSE REACTIONS
6.1     Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Men with Primary or Hypogonadal Osteoporosis and Postmenopausal Women with Osteoporosis The safety of FORTEO in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, double-blind, placebo-controlled trials of 1,382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years) [see Clinical Studies (13.1, 13.2)]. The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to FORTEO and 691 patients to placebo. All patients received 1,000 mg of calcium plus at least 400 IU of vitamin D supplementation per day.

The incidence of all- cause mortality was 1% in the FORTEO group and 1% in the placebo group. The incidence of serious adverse events was 16% in the FORTEO group and 19% in the placebo group. Early discontinuation due to adverse events occurred in 7% in the FORTEO group and 6% in the placebo group.

Table 1 lists adverse events from these two trials that occurred in ≥2% of FORTEO-treated and more frequently than placebo- treated patients.

Table 1: Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients and in More FORTEO-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality
FORTEO             Placebo
N=691            N=691
Event Classification                                                     (%)              (%) Body as a Whole
Pain                                                                    21.3              20.5 Headache                                                                  7.5              7.4 Asthenia                                                                  8.7              6.8 Neck pain                                                                 3.0              2.7 Cardiovascular
Hypertension                                                              7.1              6.8 Angina pectoris                                                           2.5              1.6 Syncope                                                                   2.6              1.4 Digestive System
Nausea                                                                    8.5              6.7 Constipation                                                              5.4              4.5 Diarrhea                                                                  5.1              4.6 Dyspepsia                                                                 5.2              4.1 Vomiting                                                                  3.0              2.3 Gastrointestinal disorder                                                 2.3              2.0 Tooth disorder                                                            2.0              1.3 Musculoskeletal
Arthralgia                                                              10.1               8.4 Leg cramps                                                                2.6              1.3 Nervous System
Dizziness                                                                 8.0              5.4 Depression                                                                4.1              2.7 Insomnia                                                                  4.3              3.6 Vertigo                                                                   3.8              2.7 Respiratory System
Rhinitis                                                                  9.6              8.8 Cough increased                                                           6.4              5.5 Pharyngitis                                                               5.5              4.8 Dyspnea                                                                   3.6              2.6 Pneumonia                                                                 3.9              3.3 Skin and Appendages
Rash                                                                      4.9              4.5 Sweating                                                                  2.2              1.7 

Laboratory Findings
Serum Calcium — FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was 11% of women and 6% of men treated with FORTEO compared to 2% of women and 0% of the men treated with placebo. The percentage of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.


Urinary Calcium — FORTEO increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo [see Clinical Pharmacology (11.2)].

Serum Uric Acid — FORTEO increased serum uric acid concentrations. In clinical trials, 3% of FORTEO-treated patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo-treated patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.

Renal Function — No clinically important adverse renal effects were observed in clinical studies. Assessments included creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; and examination of urine sediment.

Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of FORTEO in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥5 mg per day prednisone or equivalent for a minimum of 3 months [see Clinical Studies (13.3)].The duration of the trial was 18 months with 214 patients exposed to FORTEO and 214 patients exposed to an oral daily bisphosphonate (active control). All patients received 1,000 mg of calcium plus 800 IU of vitamin D supplementation per day.

There was no increase in mortality in the FORTEO group compared to the active control group. The incidence of serious adverse events was 21% in FORTEO patients and 18% in active control patients, and included pneumonia (3% FORTEO, 1% active control). Early discontinuation because of adverse events occurred in 15% of FORTEO patients and 12% of active control patients, and included dizziness (2% FORTEO, 0% active control).

Adverse events reported at a higher incidence in the FORTEO group and with at least a 2% difference in FORTEO-treated patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively.

6.2      Immunogenicity
As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other teriparatide products may be misleading.

In the clinical trial of postmenopausal women with osteoporosis [see Clinical Studies (13.1)], antibodies that cross reacted with teriparatide were detected in 3% of women (15/541) who received FORTEO. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.

6.3    Postmarketing Experience
Adverse Reactions from Postmarketing Spontaneous Reports
The following adverse reactions have been identified during postapproval use of FORTEO. 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 bone tumor and osteosarcoma have been reported rarely in the postmarketing period [see Warnings and Precautions (5.2)].
• Hypercalcemia: greater than 13 mg/dL has been reported with FORTEO use.

Adverse events reported since market introduction that were temporally related to FORTEO therapy include the following:
• Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria
• Investigations: Hyperuricemia
• Respiratory System: Acute dyspnea, chest pain
• Musculoskeletal: Muscle spasms of the leg or back
• Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema 
Adverse Reactions from Observational Studies to Assess Incidence of Osteosarcoma Two osteosarcoma surveillance safety studies (U.S. claims-based database studies) were designed to obtain data on the incidence rate of osteosarcoma among FORTEO-treated patients. In these two studies, three and zero osteosarcoma cases were identified among 379,283 and 153,316 FORTEO users, respectively. The study results suggest a similar risk for osteosarcoma between FORTEO users and their comparators. However, the interpretation of the study results calls for caution owing to the limitations of the data sources which do not allow for complete measurement and control for confounders.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il