Histamine Dihydrochloride

Ceplene (histamine dihydrochloride) is used with low-dose interleukin-2 (IL-2) as an immunotherapy that aims to trigger immune destruction of residual myeloid leukaemic cells and so prevent relapse. Its role is to protect the lymphocytes, in particular natural killer (NK) cells and T cells, that carry out this destruction.

Mechanism of Action

• Role of IL-2: promotes the functions of NK cells and T cells by activating their anti-leukaemic properties and by expanding these cell populations.
• Role of Ceplene: protects the IL-2-activated NK cells and T cells. The mechanism by which it improves their anti-leukaemic function is not completely established. It is considered to work by inhibiting reactive oxygen species (oxygen free radicals), which are made by monocytes, macrophages and granulocytes and which trigger dysfunction and apoptosis in NK and T cells.
• Target: Ceplene inhibits NADPH oxidase, the enzyme that starts the formation and release of reactive oxygen species from phagocytes, so less oxygen-radical damage reaches the NK and T cells.
• Vascular effects of histamine: histamine acts on H1 and H2 receptors to widen arteries and capillaries and to raise capillary permeability, which accounts for flushing and a fall in blood pressure; it also stimulates gastric acid secretion.
• Clinical studies: Ceplene was studied for maintaining remission in adults with AML in two clinical studies, an exploratory study in 39 patients and a multinational phase 3 trial.

Pharmacokinetics

• Absorption: rapidly absorbed after subcutaneous injection, with peak plasma concentration about 10 minutes after the end of the injection. Concentrations were highly variable between studies and within healthy-volunteer and patient groups.
• Distribution: variability in exposure was greater in patients than in healthy subjects, and overall exposure was higher in patients, though not significantly. It is not known whether histamine crosses the placenta.
• Metabolism and elimination: eliminated by metabolism in kidney, liver and other tissues, mainly by histamine-N-methyltransferase and diamine oxidase; the metabolites are excreted mainly in urine. Mean half-life in patients was 0.75 to 1.5 hours.
• Special populations: age and weight have no significant effect. Clearance is almost twice as high in women, giving considerably lower exposure than in men. Renal impairment hardly changes pharmacokinetics, but in severe impairment blood pressure falls at histamine levels that have little effect in others. In moderate and severe hepatic impairment plasma levels are considerably higher.

• Acute myeloid leukaemia (AML): maintenance therapy in adult patients with AML in first remission who are concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not been fully demonstrated in patients older than 60.

• Hypersensitivity to histamine dihydrochloride or to any of the excipients.
• Significantly compromised cardiac function, for example NYHA class III or IV.
• Systemic steroid therapy, clonidine or H2 blocking agents.
• Previous allogeneic stem cell transplant.
• Pregnancy.
• Breastfeeding.

Almost all patients in the AML studies had reactions at least possibly related to IL-2 and Ceplene. The most common, in 30% or more of patients, were flushing, headache, fatigue, injection site granuloma, pyrexia and injection site erythema. The frequencies below come from 280 patients treated with low-dose IL-2 and Ceplene.

Very common (≥1/10): upper respiratory tract infections; eosinophilia, thrombocytopenia; headache, dizziness, dysgeusia; tachycardia; flushing, hypotension; cough, dyspnoea; nausea, dyspepsia, diarrhoea; rash; arthralgia, myalgia; injection site granuloma, injection site erythema, injection site reaction, injection site pruritus, injection site inflammation, injection site pain; fatigue, pyrexia, feeling hot, influenza-like illness, chills.

Common (≥1/100 to <1/10): pneumonia; leucopenia, neutropenia; anorexia; insomnia; palpitations; nasal congestion; vomiting, upper abdominal pain, dry mouth, gastritis, abdominal distension; erythema, hyperhidrosis, night sweats, pruritus; pain in extremity, back pain; injection site urticaria, bruising, rash and swelling; asthenia; chest pain.

In studies in other cancers, using 1 mg twice daily and different IL-2 and interferon-alfa regimens, further reactions were seen. Very common were decreased appetite, anxiety, dry skin, malaise, peripheral oedema and weight loss; common were anaemia, hypothyroidism, dehydration, depression, paraesthesia, vertigo, hot flush, wheezing, constipation, abdominal distension, stomatitis, injection site fibrosis and pain.

Important serious reactions are severe hypotension, tachycardia and syncope, particularly after a rapid injection or an injection into a vascular space.

When Ceplene is used with IL-2, the IL-2 SmPC is also followed for its own interactions.

• Must not be used: H2 receptor antagonists with an imidazole structure similar to histamine, such as cimetidine; systemic steroids; clonidine.
• Use with caution: beta-blockers and other antihypertensive medicines, and any medicine with cardiotoxic or blood pressure-lowering effects, which may increase Ceplene toxicity.
• Avoid: H1-blocking antihistamines and neuroleptics (antipsychotics) with H1-blocking properties, which may reduce efficacy; tricyclic antidepressants, which may have H1 and H2 blocking properties; monoamine oxidase inhibitors, antimalarial and anti-trypanosomal substances, which may alter Ceplene metabolism.
• Histamine-releasing agents: neuromuscular blocking agents, narcotic analgesics and various contrast media can release endogenous histamine, so before diagnostic or surgical procedures the additive effect of Ceplene is considered.

Ceplene maintenance therapy is started after consolidation therapy is complete, in patients also treated with IL-2, under the supervision of a physician experienced in managing acute myeloid leukaemia. It is for subcutaneous use only.

Recommended Regimen

• IL-2 (aldesleukin): 16,400 IU/kg (1 µg/kg) as a subcutaneous injection twice daily, 1 to 3 minutes before Ceplene.
• Ceplene: one 0.5 mL dose (0.5 mg) 1 to 3 minutes after each IL-2 injection, by slow subcutaneous injection at no more than 0.1 mL per minute; 5 minutes is usual, and it may be lengthened to up to 15 minutes. It can be given by an ambulatory infusion syringe pump or by controlled manual injection with a timer.
• Cycles: 10 treatment cycles, each of 21 days (3 weeks) of twice-daily treatment. Cycles 1 to 3 are each followed by a 3-week treatment-free period, and cycles 4 to 10 by a 6-week treatment-free period.
• Spacing: the two daily doses are at least 6 hours apart. The patient rests for 20 minutes after each Ceplene injection.
• Injection site: preferably the thighs or abdomen; Ceplene is not injected in the same anatomic region as IL-2.
• Preparation: patients are given capped polypropylene syringes and shown how to draw up 0.5 mL. The solution must be clear and colourless.

Who Gives the Injections

• The first dose of Ceplene and IL-2, on day 1 of the first cycle, is given in the clinic under the direct supervision of a physician, with vital signs (pulse, blood pressure, respiratory rate) monitored. A patient with a significant change in vital signs continues to be monitored at later treatments.
• Later injections may be self-administered at home by a patient who clearly understands the precautions and has shown adequate injection skills.
• Injections are preferably given in a supervised setting, in the presence of an adult family member, friend or other carer who can respond if signs of hypotension appear.

Dose Modification

• Dose changes for Ceplene and IL-2 follow individual tolerance, are addressed early and can be temporary or permanent. For Ceplene-related toxicity such as hypotension or headache, the injection time can be extended from 5 to a maximum of 15 minutes.
• Grade 1 events: no change, except grade 1 neurological toxicity and grade 1 generalised toxic dermatitis.
• Neurological toxicity: grade 1 to 3, stop until grade 0, then resume with both Ceplene and IL-2 reduced by 20%; grade 4, consider stopping.
• Generalised toxic dermatitis: grade 1, delay 48 hours or until symptoms resolve, then full-dose Ceplene with IL-2 reduced by 20%; grade 2, reduce IL-2 by 50% (back to full dose only if symptoms do not return) and keep the two injections 60 minutes apart; grade 3 or 4, stop, resuming only after the risk and benefit are weighed.
• Grade 2 toxicity (including cardiac, renal, hepatic): stop until grade 1 and extend the injection to up to 15 minutes; for cardiac, hepatic or renal toxicity, reduce both doses by 20%.
• Grade 3 or 4 toxicity (including hypotension, arrhythmia): stop until resolved; a delay of up to one cycle can be considered.
• Persistent hypotension, headache, arrhythmia, or cardiac, hepatic or renal toxicity: extend the injection to up to 15 minutes and reduce both doses by 20%.
• Fever: IL-2 can be stopped for 24 hours and restarted 20% lower. Abnormal white-cell counts: IL-2 can be reduced by 20%, permanently if counts are abnormal again next cycle. Localised toxic dermatitis: stop until resolved, then Ceplene at full dose and IL-2 at 50%.

Special Populations

• Elderly: efficacy has not been fully demonstrated in patients older than 60.
• Renal impairment: no dose reduction is normally needed, but patients may be more sensitive to the blood pressure-lowering effect; caution in severe impairment.
• Hepatic impairment: use with caution in moderate to severe impairment, where plasma levels are higher and tachycardia and lower blood pressure are more likely; dose reduction is normally not required.
• Children and adolescents: safety and efficacy under 18 years have not been established.

Hypotension and Injection Technique

Ceplene is given 1 to 3 minutes after IL-2, not at the same time. Rapid subcutaneous injection, or injection into a vascular space, may cause severe hypotension, tachycardia or syncope. Patients are monitored for complications of hypotension or hypovolaemia. If significant hypotension or related symptoms occur in later cycles, the dose is reduced and, if needed, given in hospital until home administration is again possible.

Heart and Circulation

Caution is needed in poorly compensated cardiac function. Patients with heart disease have their ejection fraction and wall function evaluated, by echocardiography or a nuclear stress test, before treatment and are then treated with caution.

Conditions Needing Caution

• Symptomatic peripheral arterial disease; past or present peptic or oesophageal ulcer with a history of bleeding (a proton pump inhibitor may be considered); clinically significant renal disease; stroke within the last 12 months.
• Clinically significant infection needing antibiotics, antifungals or antivirals, or anti-infective treatment completed within 14 days before starting (prophylaxis excepted).
• A history of autoimmune disease, including systemic lupus, inflammatory bowel disease, psoriasis and rheumatoid arthritis.
• Standard haematology and blood chemistry tests are recommended during treatment.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential and sexually active men must use effective contraception during treatment with Ceplene and IL-2.
• Pregnancy: no clinical data. Animal studies showed reproductive toxicity only at doses toxic to the mother. Ceplene with IL-2 must not be used in pregnancy.
• Breastfeeding: it is unknown whether histamine passes into breast milk. Ceplene with IL-2 must not be used while breastfeeding.
• Fertility: no clinical data; animal studies showed only a slight reduction in implantations and viable foetuses. The IL-2 SmPC covers IL-2 itself.

Effect on Driving

Ceplene has a moderate influence on the ability to drive and use machines: hypotension can cause dizziness, light-headedness and blurred vision. Patients should not drive or operate machines for at least 1 hour after receiving Ceplene.

The SmPC gives one storage instruction: do not freeze. Ceplene is supplied as 14 type I glass vials (2 mL, with bromobutyl rubber stopper and aluminium flip-off seal) per carton, each holding 0.5 mL of solution plus overfill. Check that the solution is clear and colourless before use; dispose of unused product according to local requirements.

3 years.

Prescription only (Rx), on restricted medical prescription (Annex II B), under the supervision of a physician experienced in managing acute myeloid leukaemia. The first injection is given in the clinic; later injections may be self-administered at home by a suitably trained patient. Ceplene is therefore supplied to the patient or to the treating clinic on prescription.