Adverse reactions : תופעות לוואי

4.8. Undesirable effects
Occurrence and severity of undesirable effects depend on dose level and frequency of Methotrexate administration. However, as severe adverse reactions may occur even at lower doses, it is indispensable that the doctor monitors patients regularly at short intervals.

Most undesirable effects are reversible if recognised early. If such adverse reactions occur, dose should be reduced or therapy be interrupted and appropriate countermeasures should be taken (see section 4.9). Methotrexate therapy should only be resumed with caution, under close assessment of the necessity for treatment and with increased alertness for possible reoccurrence of toxicity.

Frequencies in this table are defined using the following convention:  very common (≥ 1/10) common (≥ 1/100 < 1/10), uncommon (≥ 1/1,000 < 1/100), rare (≥ 1/10,000 < 1/1,000), very rare(< 1/10,000) , not known (cannot be estimated from the available data).
Further details are given in the following table. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness

The following adverse reactions may occur:
Very common     Common           Uncommon             Rare            Very rare           Not known Infections and                                                                   Sepsis, opportunistic infestations                                                                     infections (may be fatal in some cases),
infections caused by the cytomegaly virus.
Furthermore,
nocardiosis,
histoplasma and cryptococcus mycosis and disseminated
herpes simplex have been reported
Cardiac                                                 Pericarditis, disorders                                               pericardial effusion,
pericardial tamponade
Blood and       Leukocytopenia    Pancytopenia,         Megaloblastic    Severe courses of lymphatic       thrombocytopeni   agranulocytosi,       anaemia          bone marrow system          a, anaemia        haematopoietic                         depression, aplastic disorders                         disorders                              anaemia.
Lymphadenopathy,
lymphoproliferative disorders (partly reversible see
“description” below),
eosinophilia and neutropenia.
First signs for these life-threatening complications maybe: fever, sore throat,
ulcerations of oral mucosa, flu-like complaints, strong exhaustion,
dermatorrhagia.
Use of methotrexate should be interrupted immediately if the number of blood cells significantly declines
Immune                            Allergic reactions,                    Immunosuppression system                            anaphylactic                           Hypogamma- disorders                         shock                                  globulinaemia Allergic vasculitis
Metabolism                        Diabetes mellitus and nutrition disorders
Psychiatric                       Depression            Mood             Insomnia disorders                                               fluctuations
Nervous         Headache,         Vertigo,                               Pain, muscular            Leukoen- system          fatigue,          confusion,                             asthenia or               cephalopathy, disorders       drowsiness        seizures                               paresthesia of the        Aphasia, paresis, extremities, changes      hemiparesis in sense of taste
(metallic taste), acute aseptic meningitis with meningism
(paralysis, vomiting)
Eye disorders                                           Servere visual   Conjunctivitis, disturbances     retinopathy

Ear and labyrinth disorders
Neoplasms                         Individual cases benign,                           of lymphoma,
malignant                         which abated in a and                               number of cases unspecified                       once
(incl cysts                       methotrexate and polyps)                       treatment had
been discontinued. In a recent study, it was not possible to establish that methotrexate therapy increases the incidence of lymphomas
Vascular                                              Vasculitis (as       Hypotension, disorders                                             severe toxic         thromboemboli symptom)             c events
(including arterial and cerebral thrombosis,
thrombophlebit is, deep vein thrombosis,
retinal vein thrombosis,
pulmonary embolism).
Respirator,                     Pulmonary             Pulmonary            Pharyngitis,      Pneumocystis carinii    Epistaxis thoracic and                    complications         fibrosis             apnoea,           pneumonia and other     Pulmonary mediastinal                     due to interstitial                        bronchial         pulmonary infections,   alveolar disorders                       alveolitis/pneum                           asthma-like       chronic                 haemorrhage* onitis and related                         reactions with    Obstructive *(has been deaths                                     cough,            pulmonary disease.
reported for
(independent of                            dyspnoe           Pleural effusion        methotrexate dose                                       and used in and duration of                            pathological rheumatologic methotrexate                               findings in the and related treatment).                                lung function indications)
Typical                                    test symptoms may be: general illness;
dry,irritating cough; shortness of breath progressing to rest dyspnoea,
chest pain, fever.
If such complications are suspected,
Methotrexate treatment must be discontinued immediately and infections
(including pneumonia) must be excluded.

Gastrointestin   Loss of        Diarrhoea             Gastrointestinal     Enteritis,        Haematemesis, toxic al disorders     appetite,      (especially           ulcers and           melaena           megacolon nausea,        during the first      bleeding.            Gingivitis, vomiting,      24-48 hours after                          malabsorption abdominal      administration of pain,          Methotrexate).
inflammation and
ulcerations of the mucous membrane of mouth and throat
(especially during the first
24-48 hours after administration of
Methotrexate).
Stomatitis,
dyspepsia
Hepato-biliary   Increase in        Development of       Acute hepatitis   Reactivation of disorders        liver-related      liver fattening,     and               chronic hepatitis, enzymes            fibrosis and         hepatotoxicity    acute liver (ALAT [GPT],       cirrhosis (occurs                      degeneration, hepatic ASAT [GOT],        frequently despite                     failure alkaline           regularly                              Furthermore, herpes phosphatase        monitored,                             simplex hepatitis and and bilirubin).    normal values of                       liver insufficiency liver enzymes);
have been observed drop of serum albumin.                               (also see the notes regarding liver biopsy in section4.4).
Skin and         Exanthema,          Urticaria,            Increased         Acute paronychia,       Skin exfoliation subcutaneou      erythema, itching   photosensibility,     pigmentary        furunculosis,           /dermatitis s tissue                             enhanced              changes of        telangiectasia          exfoliative disorders                            pigmentation of       nails,            hidradenitis the skin, hair        onycholysis,
loss, disturbed       acne,
wound healing,        petechiae,
increase of           ecchymoses,
rheumatic             erythema nodules, herpes       multiforme,
zoster, skin          cutaneous ulceration in         erythematous psoriatic patients,   eruptions.
painful lesions of psoriatic plaque
(Psoriatic lesions can exacerbate due to UV radiation during concomitant treatment with methotrexate
(also see section
4.4); severe toxic reactions: vasculitis,
herpetiform eruption of the skin, Stevens-
Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)
Musculoskele                         Arthralgia,           Stress fracture                           Osteonecrosis of tal system,                          myalgia,                                                        jaw (secondary connective                           osteoporosis                                                    to tissue and                                                                                           lymphoproliferati bone                                                                                                 ve disorders) disorders
Renal and                            Inflammation and      Renal failure,    Proteinuria             Nephropathy urinary                              ulceration of the     oliguria,
disorders                            urinary bladder       anuria,
(possibly with        azotaemia haematuria),
dysuria.
General                              After                                   Fever, Subcutaneous disorders and                        intramuscular use                       administration of administratio                        of methotrexate,                        methotrexate shows n site                               local adverse                           good local tolerance.
conditions                           reactions                               Only mild local skin (burning                                reactions, the number sensation) or                           of which decreased in damage (sterile                         the course of formation of                            treatment, have been abscess,                                observed so far.
destruction of fatty tissue) can occur at the site of injection.
Investigations
Reproductive                                   Inflammation and    Oligospermia,   Loss of libido, system and                                     ulceration of the   menstruation    impotence, vaginal breast                                         vagina              disorders       discharge, infertility disorders                                                                          Gynaecomastia 


The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.
When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions were observed, decreasing during therapy.


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/