Raltitrexed

Pregnancy should be avoided if either partner is receiving raltitrexed. It is also recommended that conception should be avoided for at least 6 months after cessation of treatment.

Raltitrexed should not be used during pregnancy or in women who may become pregnant during treatment. Pregnancy should be excluded before treatment with raltitrexed is started.

Raltitrexed should not be given to women who are breast-feeding.

Fertility

Fertility studies in the rat indicate that raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. Raltitrexed caused embryo lethality and foetal abnormalities in pregnant rats.

Raltitrexed may cause malaise or asthenia following infusion and the ability to drive/use machinery could be impaired whilst such symptoms continue.

As with other cytotoxic drugs, raltitrexed may be associated with certain adverse drug reactions. These mainly include reversible effects on the haemopoietic system, liver enzymes and gastrointestinal tract. The following list presents the possible adverse drug reactions occurring with raltitrexed treatment.

In this section undesirable effects are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data).

Adverse drug reactions in patients treated with raltitrexed for advanced colorectal carcinoma divided by System Organ Class and frequency:

Infections & infestations

Common: Cellulitis, Sepsis, Flu-like syndrome

Blood and lymphatic disorders

Very Common: Leukopenia (neutropenia in particular)^a,b, Anaemia^a

Common: Thrombocytopenia^a,b

Metabolism and Nutrition Disorders

Very Common: Anorexia

Common: Dehydration

Nervous system disorders

Common: Headache, Hypertonia (usually muscular cramps), Taste perversion

Eye disorders

Common: Conjunctivitis

Gastrointestinal disorders

Very Common: Nausea^c, Diarrhoea^d,e, Vomiting^c,e, Constipation, Abdominal Pain

Common: Stomatitis, Dyspepsia, Mouth ulceration

Frequency unknown: Gastrointestinal Bleeding^f,g

Hepato-biliary disorder

Common: Hyperbilirubinemia

Skin & subcutaneous tissue disorders

Very Common: Rash

Common: Alopecia, Pruritus, Sweating

Uncommon: Desquamation

Musculoskeletal, Connective tissue & bone disorders

Common: Arthralgia

General disorders and administration site conditions

Very Common: Asthenia^h, Fever^h, Mucositis

Common: Peripheral oedema, Pain, Malaise

Investigations

Very Common: AST increasedⁱ, ALT increasedⁱ

Common: Weight loss, Alkaline phosphatase increased

^a Leukopenia (neutropenia in particular), anaemia and thrombocytopenia, alone or in combination, are usually mild to moderate and occur in the first or second week after treatment and recover by the third week.
^b Severe (WHO grade 3 and 4) leukopenia (neutropenia in particular) and thrombocytopenia of WHO grade 4 can occur and may be life-threatening or fatal especially if associated with signs of gastrointestinal toxicity.
^c Nausea and Vomiting are usually mild (WHO grade 1 and 2), occur usually in the first week following the administration of raltitrexed, and are responsive to antiemetics.
^d Diarrhoea is usually mild or moderate (WHO grade 1 and 2) and can occur at any time following the administration of raltitrexed. However, severe diarrhoea (WHO grade 3 and 4) can occur and may be associated with concurrent haematological suppression especially leukopenia (neutropenia in particular). Subsequent treatment may need to be discontinued or dose reduced according to the grade of toxicity.
^e Diarrhoea and vomiting may be severe and if untreated may proceed to dehydration, hypovolaemia and renal impairment
^f from spontaneous reporting
^g Gastrointestinal bleeding may be associated with mucositis and/or thrombocytopenia.
^h Asthenia and fever were usually mild to moderate following the first week of administration of raltitrexed and reversible. Severe asthenia can occur and may be associated with malaise and a flu-like syndrome.
ⁱ Increases in AST and ALT have usually been asymptomatic and self-limiting when not associated with progression of the underlying malignancy.