Ceplene - histamine dihydrochloride

What is Ceplene?

Ceplene is a solution for injection containing the active substance histamine dihydrochloride ( 0.5 mg / 0.5 ml).

What is Ceplene used for?

Ceplene is used in combination with interleukin-2 (an anticancer medicine) in the maintenance therapy of adult patients with acute myeloid leukemia, a type of cancer that affects white blood cells. The medicine is used during the first "remission" of patients (a period without the symptoms of the disease after the first course of treatment). The efficacy of Ceplene has not been fully demonstrated in patients over the age of 60.

Because the number of patients with acute myeloid leukemia is low, the disease is considered rare, and Ceplene was designated an "orphan medicine" (a medicine used in rare diseases) on 11 April 2005.

The medicine can only be obtained with a prescription.

How is Ceplene used?

Ceplene should be administered under the supervision of a doctor experienced in the treatment of acute myeloid leukemia. The recommended dose of Ceplene is a 0.5 mg injection under the skin, twice a day, one to three minutes after the interleukin-2 injection. Ceplene and interleukin-2 should be administered for 10 cycles. The first three cycles consist of three weeks of treatment, followed by a three-week period without treatment. The next seven cycles consist of three weeks of treatment, followed by a six-week period without treatment.

The first time Ceplene is administered, it is necessary to monitor the patient's blood pressure, heart rate and lung function. Depending on the patient's response to treatment and side effects, treatment may be suspended or the dose adjusted.

Each injection of Ceplene should be administered slowly over a period of 5-15 minutes, performed in a location other than the injection of interleukin-2 and preferably in the thigh or abdomen (belly). Patients can practice self-injection after receiving specific instructions.

Ceplene should be used with caution in patients with severe kidney problems or moderate to severe liver problems. The use of Ceplene is not recommended in patients under 18 years of age due to lack of information on the safety and efficacy of the medicine in this age group.

How does Ceplene work?

The active substance in Ceplene, histamine dihydrochloride, is an immunomodulator. This means that it alters the activity of the immune system (the body's natural defenses). Histamine is a naturally occurring substance in the body that participates in many processes. In the treatment of acute myeloid leukemia, it is believed to exert a protective action on the cells of the immune system by defending them from damage. This improves the effectiveness of interleukin-2, a medicine that stimulates the immune system to attack cancer cells. When Ceplene is given with interleukin-2, it helps the immune system destroy any leukemia cells left in the body during remission. This can prolong the period of time until the return of acute myeloid leukemia.

How has Ceplene been studied?

The effects of Ceplene were first tested in experimental models before being studied in humans. Since histamine is a known substance, the company also presented data from the published literature.

The efficacy of Ceplene was tested in only one main study involving 320 adult patients with acute myeloid leukemia in remission after antileukemic treatment. Ceplene was given in combination with interleukin-2 and compared with no treatment. The main measure of effectiveness was the period of time until the return of the disease or the patient's death.

What benefit has Ceplene shown during the studies?

The combination of Ceplene and interleukin-2 was more effective than any treatment in prolonging the time period until the return of acute myeloid leukemia or until the patient's death: in patients in their first complete remission, the mean time without disease rose from 291 days without treatment to 450 days after treatment with Ceplene and interleukin-2. No effect of Ceplene and interleukin-2 was observed in patients in second or subsequent remission.

What is the risk associated with Ceplene?

The most common side effects of Ceplene (seen in more than 1 patient in 10) are eosinophilia (increased concentration of eosinophils, a type of white blood cell), thrombocytopenia (decreased blood platelets), headache, dizziness, dysgeusia ( bitter or strange taste in the mouth), tachycardia (rapid heart rate), flushes, hypotension (low blood pressure), cough, dyspnea (shortness of breath), nausea, dyspepsia (indigestion)), diarrhea, rash, arthralgia (pain at joints), myalgia (pain in the muscles), pyrexia (fever), chills, fatigue (tiredness), flu-like symptoms, feeling of heat and reactions (redness, hematoma, pain and inflammation) at the injection site. For the full list of all side effects reported with Ceplene, see the Package Leaflet.

Ceplene should not be used in people who may be hypersensitive (allergic) to histamine dihydrochloride or any of the other components. The medicine should not be used in patients with severe heart problems or in women who are pregnant or breastfeeding. The medicine should also not be used in patients who have received a donor bone marrow transplant or who are taking steroids (to reduce or prevent inflammation), clonidine (to reduce high blood pressure), or H2 receptor blockers in the 'histamine (for the treatment of stomach ulcer, indigestion or heartburn).

Why has Ceplene been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that Ceplene's benefits are greater than its risks in maintenance therapy for adult patients with acute myeloid leukemia when used in combination with interleukin-2. The committee recommended that Ceplene be given marketing authorization.

Ceplene was authorized in "exceptional circumstances" because, being a rare disease, it was not possible to obtain complete information on the medicine. Every year the EMEA will review any new information that may be available and, if necessary, this summary will be updated.

What information is still awaited for Ceplene?

The company will conduct other studies to look in more detail at the efficacy of the combination of Ceplene and interleukin-2 and the way this combination works.