Metoject® PEN solution for injection pre-filled pen can only be given by the subcutaneous route. Methotrexate must only be used once a week.   

The first injection of subcutaneous methotrexate PEN should be performed under direct medical supervision. However, your doctor may decide that you can learn how to inject subcutaneous methotrexate PEN yourself. You will receive appropriate training for you to do this.

The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Folic acid supplementation may be considered according to current treatment guidelines.

• Hypersensitivity to the active substance or to any of the following excipients
  • Sodium chloride
  • Sodium hydroxide (for pH adjustment)
  • Hydrochloric acid (for pH adjustment)
  • Water for injections
• Severe liver impairment
  • Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. If bilirubin is 5 mg/dl (85.5 μmol/l), methotrexate is contraindicated
• Alcohol abuse
• Severe renal impairment
  • Creatinine clearance less than 30 ml/min
• Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia
• Serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,
• Ulcers of the oral cavity and known active gastrointestinal ulcer disease,
• Pregnancy and breastfeeding (see below)
• Concurrent vaccination with live vaccines

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester.

• Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

• Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.
• Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in disease-matched patients treated with drugs other than methotrexate.

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter.

• Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential.
• The absence of pregnancy must be confirmed before Metoject® PEN is used. If women of a sexually mature age are treated, effective contraception must be performed during treatment and for at least six months after.

Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 3 months after cessation of methotrexate. Men should not donate semen during therapy or for 3 months following discontinuation of methotrexate.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver function tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.

Key Adverse Events.

Frequency	Side Effect
Very common: may affect more than 1 in 10 people	Inflammation of the mouth lining, indigestion, feeling sick, loss of appetite, abdominal pain. Abnormal liver function test (ASAT, ALAT, bilirubin, alkaline phosphatase).
Common: may affect up to 1 in 10 people	Mouth ulcers, diarrhoea. Rash, reddening of the skin, itching. Headache, tiredness, drowsiness. Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets.
Uncommon: may affect up to 1 in 100 people	Throat inflammation. Inflammation of the bowels, vomiting, inflammation of pancreas, black or tarry stools. Gastrointestinal ulcers and bleeding. Sunburn-like reactions due to increased sensitivity of the skin to sunlight, loss of hair, increased Number of rheumatic nodules, skin ulcer, shingles, inflammation of blood vessels, herpes-like skin rash, hives. Onset of diabetes mellitus. Dizziness, confusion, depression. Decrease in serum albumin. Decrease in the number of all blood cells and platelets. Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function, disturbed urination. Joint pain, muscle pain, reduction of bone mass.
Rare: may affect up to 1 in 1,000 people	Inflammation of gum tissue. Increased skin pigmentation, acne, blue spots on the skin due to vessel bleeding (ecchymosis, petechiae), allergic inflammation of blood vessels. Decreased number of anti-bodies in the blood. Infection (incl. reactivation of inactive chronic infection), red eyes (conjunctivitis). Mood swings (mood alterations). Visual disturbances. Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart. Obstruction of cardiac filling due to fluid in the sac around the heart. Low blood pressure. Formation of scar tissue in the lung (pulmonary fibrosis)shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung. Stress fracture. Electrolyte disturbances. Fever, wound-healing impairment.
Very rare: may affect up to 1 in 10,000 people	Acute toxic dilatation of the gut (toxic megacolon). Increased pigmentation of the nails, inflammation of the cuticles (acute paronychia), deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels. Pain, loss of strength or sensation of numbness or tingling/having less sensitivity to stimulation than normal, changes in taste (metallic taste), convulsions, paralysis, meningism. Impaired vision, non-inflammatory eye disorder (retinopathy). Loss of sexual drive, impotence, male breast enlargement, defective sperm formation (oligospermia), menstrual disorder, vaginal discharge. Enlargement of lymphatic nodes (lymphoma). Lymphoproliferative disorders (excessive growth of white blood cells).