Low Dose Methotrexate for Rheumatoid Arthritis

There is some uncertainty about the precautions that need to be taken while preparing and administering low dose methotrexate for rheumatoid arthritis (RA) patients either in the ward or at home.

Like most drugs, the dose, routes of administration and toxicity vary depending on the condition and course of treatment. The precautions required during administration differ accordingly. Hence, providing patients and medical staff with accurate information is critical for the safety of patients, medical staff, and third-party family members. It will also help in the compliance and adherence of patients to treatment.

Weekly low dose methotrexate is the first-line disease-modifying anti-rheumatic drug (DMARD) in the treatment of RA. Also, methotrexate can be used for the treatment of other conditions such as psoriatic arthritis, juvenile idiopathic arthritis, and systemic vasculitis.

Methotrexate (< 25 mg/m²) is well absorbed from the gastrointestinal tract with variable inter-individual bioavailability of 70%. However, at larger doses, absorption may become erratic and incomplete. For this reason, parenteral administration may be appropriate in cases of poor efficacy or tolerability. Peak serum levels may be achieved in one to four hours following oral administration and within 0.5 to two hours following intravenous or intramuscular administration. Methotrexate is widely distributed into body tissues and concentrates in the kidneys, liver and gastrointestinal tract. It also distributes into third space compartments, e.g., ascites or pleural effusions. It is slowly released from these spaces, which results in a prolonged terminal phase half-life and unexpected toxicity. In patients with large third space accumulation, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Methotrexate is mainly excreted unchanged by the kidneys (70%), and small amounts appear in the faeces. Methotrexate cannot be absorbed via the skin as it is not lipophilic.

The verbal and nonverbal communications of healthcare professionals contain several unintentional negative recommendations that may trigger a nocebo response. There are several methotrexate misconceptions that might be held by patients and health professionals since available consumer medicine information (CMI) list many adverse effects that might be confusing to patients.

Myth: Low dose methotrexate is chemotherapy

Methotrexate is used in chemotherapy protocols at regimens as low as 30mg/m² and up to 12,000mg/m² with a maximum dose of 20,000mg (usually over 500mg/m²). It can be given as a single agent or in combination with other cytotoxic medications according to each chemotherapy protocol. For rheumatic diseases, methotrexate is typically used in low weekly oral or parenteral regimens. Doses range from 10 to 30 mg weekly (usually less than 10 mg/m² weekly) which cannot be considered as chemotherapy.

Myth: Low dose methotrexate is cytotoxic

Methotrexate as chemotherapy must be prepared under cytotoxic guidelines. The cytotoxic guidelines do not apply however to the preparation and administration of low dose methotrexate in non-neoplastic diseases. Methotrexate is not a vesicant or an irritant parenteral drug. Conventional and post-needle stick precautions (eye, mask, and glove) are mandatory for staff administering injected methotrexate. However, there is not any evidence to support the notion that health care workers with reproductive capacity are harmed by administering low dose methotrexate for RA patients. Therefore, there is no reproductive risk to medical staff or their partners from administering methotrexate to RA patients.

Methotrexate may be excreted in body fluids and waste, including blood, urine, faeces, vomit, and semen. As per CMI and product information (PI), patients are often advised to take some precautions to protect other people while they are receiving methotrexate injection. This includes flushing the toilet twice to dispose of body fluids and waste, wearing gloves to clean any spill of body fluids, discarding towels into a separate waste bag, washing linen or clothing that is heavily contaminated with body fluids or waste separately from other items, and use of a barrier method of contraception such as a condom. Such precautions apply when methotrexate is given as chemotherapy at doses over 500mg/m².  In the absence of any data related to low dose weekly methotrexate, it is recommended that normal standards of personal hygiene are the main precautions for third parties around patients on low weekly methotrexate for RA. The practical likelihood of exposures through contact with methotrexate-treated RA patients’ body fluids resulting in methotrexate toxicity is likely to be negligible with standard personal hygiene.

Myth: Self-administration of methotrexate is unsafe

Self-administration is very safe and it should always be recommended for RA patients. However, patients should receive proper education on the technique of self-injection. Self-administration will dismiss any escalating concerns that might be raised regarding exposure to third parties. Trexject® single-use prefilled syringe can be recommended as an easy and convenient way of self–administration by RA patients or even by medical staff at any healthcare facility.

Myth: RA patients on low dose methotrexate should avoid any social contact with pregnant women

Certainly, methotrexate is a pregnancy category D drug and should not be administered to pregnant women as it can cause miscarriage or foetal deformity. Women of child-bearing age should use effective contraception while taking methotrexate and women planning to become pregnant should stop taking methotrexate three months before attempting to conceive. However, the potential of a pregnant woman to have sufficient exposure to methotrexate from social contact with a methotrexate-treated individual with RA is negligible. Therefore, there is negligible risk in already pregnant women exposed to partners’ body fluids. Based on current evidence, low-dose methotrexate seems safe when the father is taking methotrexate.

Myth: Methotrexate must not be taken in combination with NSAID

Methotrexate is often prescribed with (NSAIDs) or cyclo-oxygenase-2 (COX-2) inhibitors for the relief of RA-associated pain and for its inflammatory component. However, there is a major drug interaction in most dispensing software and reference texts to avoid the combination of an NSAID and methotrexate. Providing patients with inaccurate information can lead to confusion as they are often advised to avoid this combination. This interaction is only significant if there is any underlying kidney disease or if the patient is receiving a high dose of methotrexate as chemotherapy. However, there is no specific evidence to completely avoid the combination of NSAIDs and methotrexate. Due to the renal clearance of methotrexate, renal function should be monitored and the dose of methotrexate appropriately adjusted if needed.