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.
Treatment of Osteoporosis in Men and Postmenopausal Women
The safety of teriparatide 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). The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to teriparatide 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 teriparatide group and 1% in the placebo group. The incidence of serious adverse events was 16% in teriparatide patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 7% of teriparatide patients and 6% of placebo patients.
Table 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in ≥2% of teriparatide-treated and more frequently than placebo-treated patients.

Table 1. Percentage of Patients with Adverse Events Reported by at Least 2% of Teriparatide-Treated Patients and in More Teriparatide-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men (Adverse Events are Shown Without Attribution of Causality) Teriparatide                    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 
Immunogenicity — In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) receiving teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.

Laboratory Findings
Serum Calcium —teriparatide 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 teriparatide administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with teriparatide. The number of patients treated with teriparatide whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.
Urinary Calcium —teriparatide increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with teriparatide and placebo [see Clinical Pharmacology (12.2)].
Serum Uric Acid —teriparatide increased serum uric acid concentrations. In clinical trials, 3% of teriparatide patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo 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.
Studies in Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of teriparatide 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. The duration of the trial was 18 months with 214 patients exposed to teriparatide and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1,000 mg of calcium plus 800 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 4% in the teriparatide group and 6% in the active control group. The incidence of serious adverse events was 21% in teriparatide patients and 18% in active control patients, and included pneumonia (3% teriparatide, 1% active control). Early discontinuation because of adverse events occurred in 15% of teriparatide patients and 12% of active control patients, and included dizziness (2% teriparatide, 0% active control).
Adverse events reported at a higher incidence in the teriparatide group and with at least a 2% difference in teriparatide-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 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of teriparatide. 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.
• Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period.
The causality to teriparatide use is unclear. Long term osteosarcoma surveillance studies are ongoing [see Warnings and Precautions (5.1)]
• Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with teriparatide use.
Adverse events reported since market introduction that were temporally (but not necessarily causally) related to teriparatide 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 
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

Additionally, you should also report to Kamada Ltd. to email address: pharmacovigilance@kamada.com