Histamine

H₁ receptor blocking antihistamines or neuroleptics (anti-psychotics) with H₁ receptor blocking properties that might decrease efficacy of histamine should be avoided.

Monoamine oxidase inhibitors, anti-malarial, and anti-trypanosomal active substances may alter the metabolism of Ceplene and should be avoided.

Beta-blockers and other anti-hypertensive agents should be used with caution during treatment with histamine. Concurrent administration of medicinal products with cardiotoxicity or blood pressure lowering effects may increase the toxicity of histamine.

Patients with clinically significant infection requiring the use of antibiotics, antifungals, or antivirals, or who have completed prior anti-infectious therapy within 14 days of starting treatment should be treated with caution unless the use of antibiotics and antivirals were for prophylaxis purposes.

It has been noted that neuromuscular blocking agents, narcotic analgesics, and various contrast media can induce the release of endogenous histamine; therefore in patients undergoing diagnostic or surgical procedures, the additive effect of histamine treatment should be considered prior to the procedure.

Tricyclic anti-depressants may have H₁ and H₂ receptor blocking properties and should be avoided.

Treatment with histamine in conjunction with IL-2 should be used with caution in patients with poorly compensated cardiac function. Patients with cardiac disease should be evaluated for ventricular ejection fraction and wall function by echocardiography or nuclear medicine stress test and then treated with caution.

Caution should be used for patients with any of the following: symptomatic peripheral arterial disease, past or present peptic or oesophageal ulcer disease with a history of bleeding, clinically significant renal disease and stroke within the last 12 months. Where appropriate, consideration should be made to providing concomitant treatment with a proton pump inhibitor.

Patients with a prior history of autoimmune disease (including systemic lupus, inflammatory bowel disease, psoriasis and rheumatoid arthritis) should be treated with caution. Monitoring of laboratory test results is recommended including standard haematological and blood chemistry tests.

For histamine, no clinical data on exposed pregnancies are available. Animal studies showed reproductive toxicity but only at maternotoxic doses, and did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Histamine in conjunction with IL-2 must not be used during pregnancy.

It is unknown whether histamine is excreted in human breast milk. The excretion of histamine in milk has not been studied in animals, but at maternotoxic doses in rats, offspring showed slight toxicity during early lactation. Histamine in conjunction with IL-2 must not be used during breast-feeding.

Contraception in males and females

Women of childbearing potential and sexually active men must use effective methods of contraception during treatment with histamine and IL-2.

Fertility

No clinical data are available on the effects of histamine on fertility. Animal studies revealed no adverse effects on fertility apart from a slight reduction in implantations and viable foetuses.

Histamine has moderate influence on the ability to drive and use machines. Administration of histamine can cause hypotension and may result in dizziness, light-headedness and blurred vision. Patients should not drive or operate machines for at least 1 hour after receiving histamine.

Acute myeloid leukaemia

Adverse reactions were reported to be at least possibly related to IL-2 and histamine dihydrochloride treatment in almost all patients in studies in AML.

The most common adverse reactions experienced by 30% or more of patients receiving IL-2 and histamine dihydrochloride (listed in descending order of frequency) were: flushing, headache, fatigue, injection site granuloma, pyrexia and injection site erythema.

The adverse reactions considered at least possibly related to the treatment of low-dose IL-2 with histamine dihydrochloride in AML studies (n=280 for the IL-2 and histamine dihydrochloride treatment arm) are listed below by body system organ, class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as 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), or not known (cannot be estimated from the available data).

Other oncology (advanced tumour) studies

Histamine dihydrochloride and low dose IL-2 have been investigated in other clinical studies at different doses (1.0 mg histamine dihydrochloride twice a day) and with different dose regimens of low-dose IL-2 and interferon-alfa. The following adverse reactions, not listed above, were at least possibly related to the study medicine: