Special Warning : אזהרת שימוש

5      WARNINGS AND PRECAUTIONS
5.1    Hematologic Toxicity
Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia have been observed in patients treated with CYMEVENE 500 MG. The frequency and severity of these events vary widely in different patient populations [see Adverse Reactions (6.1)]. CYMEVENE 500 MG is not recommended if the absolute neutrophil count is less than 500 cells/L, hemoglobin is less than 8 g/dL, or the platelet count is less than 25,000 cells/L. CYMEVENE 500 MG should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation.
Granulocytopenia (neutropenia) usually occurs during the first or second week of treatment but may occur at any time during treatment. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving CYMEVENE 500 MG solution for treatment of CMV retinitis.
Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving CYMEVENE 500 MG [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently in all patients, especially in patients with renal impairment and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/L at the beginning of treatment [see Dosage and Administration (2.2)].
5.2    Renal Impairment
CYMEVENE 500 MG should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)].
Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., ciclosporin and amphotericin B). Monitoring renal function during therapy with CYMEVENE 500 MG is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity [see Dosage and Administration (2.5), Drug Interactions (7), Use in Specific Populations (8.5)].
5.3    Impairment of Fertility
Based on animal data and limited human data, CYMEVENE 500 MG at the recommended human dose (RHD) may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with the use of CYMEVENE 500 MG [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
5.4   Fetal Toxicity
CYMEVENE 500 MG may cause fetal toxicity when administered to pregnant women based on findings in animal studies.
Systemic exposure of ganciclovir in animals at approximately 2 times the RHD caused fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes in animals included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with CYMEVENE 500 MG. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with CYMEVENE 500 MG [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
5.5   Mutagenesis and Carcinogenesis
Animal data indicate that ganciclovir is mutagenic and carcinogenic. CYMEVENE 500 MG should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)].
5.6 Excipients
This medicinal product contains 2 mmol (43mg) sodium per 500 mg dose. To be taken into consideration by patients on a controlled sodium diet.
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 CYMEVENE 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 CYMEVENE 500 MG and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, CYMEVENE 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 CYMEVENE 500 MG to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Maintenance Treatment Studies
Adverse Reaction                              CYMEVENE 500 MG          Ganciclovir Capsules (n=179)                     (n=326)

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 CYMEVENE 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*
CYMEVENE 500 MG †      Ganciclovir Capsules‡
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 CYMEVENE 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 CYMEVENE 500 MG, Placebo or Control
CYMEVENE 500 MG
Heart Allograft*          Bone Marrow Allograft†
CYMEVENE       Placebo      CYMEVENE        Control
500 MG (n=76) (n=73)        500 MG (n=57)    (n=55)
Neutropenia
Absolute Neutrophil
Count (ANC) per L
<500                       4%             3%           12%              6% 500-1000                   3%             8%           29%             17% Total ANC
1000/L                   7%            11%           41%             23% Thrombocytopenia
Platelet count per L
<25,000                    3%             1%           32%             28% 25,000-50,000              5%             3%           25%             37%
Total Platelet Count
50,000/L                 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 CYMEVENE 500 MG or Placebo
Heart Allograft                Bone Marrow Allograft            Bone Marrow Allograft Serum
ICM 1496                          ICM 1570                          ICM 1689 Creatinine
CYMEVENE 500       Placebo         CYMEVENE 500      Control       CYMEVENE 500       Placebo Levels
MG                                 MG                               MG (mg/dL)
(n=76)           (n=73)            (n=20)         (n=20)            (n=37)         (n=35) 
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 CYMEVENE 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 CYMEVENE 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
In addition, you may report suspected adverse reactions by sending an e-mail message to safety@tzamal-medical.co.il 

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