Adverse reactions : תופעות לוואי

6     ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
• Hematologic Toxicity [see Warnings and Precautions (5.1)]
• Renal Impairment [see Warnings and Precautions (5.2)]
• Impairment of Fertility [see Warnings and Precautions (5.3)]
• Fetal Toxicity [see Warnings and Precautions (5.4)]
• Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)] 

6.1   Clinical Trial Experience in Adult Patients
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 rates observed in practice. The most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were pyrexia, diarrhea, leukopenia, nausea, anemia, asthenia, headache, cough, decreased appetite, dyspnea, abdominal pain, sepsis, hyperhidrosis, and blood creatinine increased.

Selected adverse reactions that occurred during clinical trials of intravenous GANCICLOVIR 500 MG are summarized below, according to the participating study patient population.
Adverse Reactions in Patients with CMV Retinitis: Three controlled, randomized, phase 3 trials comparing intravenous GANCICLOVIR 500 MG and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed.
During these trials, intravenous GANCICLOVIR 500 MG or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively [see Clinical Studies (14.1)].



Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing Intravenous GANCICLOVIR 500 MG to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Maintenance Treatment Studies
Adverse Reaction                                 Intravenous           Ganciclovir Capsules GANCICLOVIR                   (n=326)
500 MG (n=179)
Pyrexia                                             48%                           38% Diarrhea                                            44%                           41% Leukopenia                                          41%                           29% Anemia                                              25%                           19% Total catheter events                               22%                            6% Catheter infection                                 9%                            4% Catheter sepsis                                    8%                            1% Other catheter related events                      5%                            1% Sepsis                                              15%                            4% Decreased appetite                                  14%                           15% Vomiting                                            13%                           13% Infection                                           13%                            9% Hyperhidrosis                                       12%                           11% Chills                                              10%                            7% Neuropathy peripheral                                9%                            8% Thrombocytopenia                                     6%                            6% Pruritus                                             5%                            6% 
Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with intravenous GANCICLOVIR 500 MG and in 8% of patients treated with ganciclovir capsules.


Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis CMV Retinitis Treatment*
Intravenous         Ganciclovir Capsules‡
GANCICLOVIR 500
MG †
Laboratory Abnormalities           5 mg/kg/day               3000 mg/day (N=175)                   (N=320)
%                         %
Neutropenia with Absolute
Neutrophil Count (ANC) per µL:
<500                                   25%                       18%
500 – <749                             14%                       17% 750 – <1000                            26%                       19% Anemia with Hemoglobin (g/dL):
<6.5 g/dL                               5%                        2%
6.5 – <8.0                             16%                       10% 8.0 – <9.5                             26%                       25% Serum Creatinine (mg/dL):
≥2.5                                    2%                        1% ≥1.5 – <2.5                            14%                       12% 

* Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 † Mean time on therapy = 103 days, including allowed re-induction treatment periods ‡ Mean time on therapy = 91 days, including allowed re-induction treatment periods 

Adverse Reactions in Transplant Recipients: There have been three controlled clinical trials of Intravenous GANCICLOVIR 500 MG for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below. Table 4 shows the frequency of neutropenia and thrombocytopenia and Table 5 shows the frequency of elevated serum creatinine values observed in these trials [see Clinical Studies (14.2)].


Table 4. Laboratory Abnormalities in Controlled Trials—Transplant Recipients who Received Intravenous GANCICLOVIR 500 MG, Placebo or Control
Intravenous
GANCICLOVIR 500 MG
Heart Allograft*          Bone Marrow Allograft†
Intravenous    Placebo       Intravenous    Control
GANCICLOVI (n=73)            GANCICLOVI      (n=55)
R 500 MG                     R 500 MG
(n=76)                       (n=57)
Neutropenia
Absolute Neutrophil
Count (ANC) per µL
<500                          4%            3%            12%               6% 500-1000                      3%            8%            29%              17% Total ANC
≤1000/µL                      7%            11%           41%              23% Thrombocytopenia
Platelet count per µL
<25,000                       3%            1%            32%              28% 25,000-50,000                 5%            3%            25%              37%
Total Platelet Count
≤50,000/µL                8%             4%           57%                  65% * Study ICM 1496. Mean duration of treatment = 28 days
† Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days 
Table 5. Serum Creatinine Levels in Controlled Trials—Transplant Recipients who Received Intravenous GANCICLOVIR 500 MG or Placebo
Heart Allograft                 Bone Marrow Allograft          Bone Marrow Allograft Serum
ICM 1496                            ICM 1570                       ICM 1689 Creatinine
Intravenous           Placebo       Intravenous           Control    Intravenous       Placebo Levels
GANCICLOVIR                         GANCICLOVIR                      GANCICLOVIR (mg/dL)
500 MG               (n=73)         500 MG              (n=20)       500 MG          (n=35) (n=76)                              (n=20)                           (n=37) 
≥2.5 mg/dL              18%                4%               20%               0%          0%               0% 
≥1.5 – <2.5              58%                69%              50%               35%         43%             44% 


Other Adverse Reactions in Clinical Trials in Patients with CMV Retinitis and in Transplant Recipients Adverse drug reactions with Intravenous GANCICLOVIR 500 MG or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below [see Clinical Studies (14)]. All these events occurred in at least 3 subjects.
Blood and lymphatic disorders: pancytopenia, bone marrow failure
Cardiac disorders: arrhythmia
Ear and labyrinth disorders: tinnitus, ear pain, deafness
Eye disorders: visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema Gastrointestinal disorders: nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth General disorders and administration site conditions: fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure
Immune system disorders: hypersensitivity
Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis
Investigations: blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased
Metabolism and nutrition disorders: weight decreased
Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor
Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams
Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria Respiratory, thoracic and mediastinal disorders: cough, dyspnea
Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash Vascular disorders: hypotension, hypertension, phlebitis, vasodilation 
6.2   Postmarketing Experience
The following adverse reactions have been identified during post-approval use of intravenous GANCICLOVIR 500 MG or ganciclovir capsules. 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.
Blood and lymphatic disorders: hemolytic anemia, agranulocytosis, granulocytopenia Cardiac disorders: cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia Congenital, familial and genetic disorders: congenital anomaly
Endocrine disorders: inappropriate antidiuretic hormone secretion
Eye disorders: cataracts, dry eyes
Gastrointestinal disorders: intestinal ulcer
Hepatobiliary disorders: cholelithiasis, cholestasis, hepatic failure, hepatitis 
Immune system disorders: anaphylactic reaction, allergic reaction, vasculitis Investigations: blood triglycerides increased
Metabolism and nutrition disorders: acidosis, hypercalcemia, hyponatremia Musculoskeletal and connective tissue disorders: arthritis, rhabdomyolysis Nervous system disorders: dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension Psychiatric disorders: irritability, hallucinations
Renal and urinary disorders: renal tubular disorder, hemolytic uremic syndrome Reproductive system and breast disorders: infertility, testicular hypotrophy Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary fibrosis Skin and subcutaneous tissues disorders: exfoliative dermatitis, Stevens-Johnson syndrome Vascular disorders: peripheral ischemia

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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