4.7.3.3. Clinical Pharmacology of Mylotarg

The patients treated with Mylotarg exhibited far less toxicity than patients who received standard chemotherapy. In contrast to standard chemotherapy, Mylotarg therapy did not result in hair loss, severe oral mucositis, or damage to the intestinal mucosa. Gemtuzumab ozogamicin is cytotoxic to the CD33 positive HL-60 human leukemia cell line. Gemtuzumab ozogamicin produces significant inhibition of colony formation in cultures of adult leukemic bone marrow cells. In preclinical animal studies, gemtuzumab ozogamicin demonstrates antitumor effects in the HL-60 human promyelocytic leukemia xenograft tumor in athymic mice.

4.7.3.4. Human Pharmacokinetics of Mylotarg

After administration of the first recommended (9 mg/m²) dose of gemtuzumab ozogamicin, the elimination half lives of total and unconjugated calicheamicin were found to about 41 and 143 hours, respectively, in 2 hour infusion. After the second dose of 9 mg/m² the half life of total calicheamicin was found to increase to about 64 hours when the area under the concentration-time curve (AUC) was about twice that in the first dose period. The AUC for the unconjugated calicheamicin increased 30% after the second dose. Age, gender, body surface area (BSA), and weight did not affect the pharmacokinetics of Mylotarg.

There is no evidence that reducing Mylotarg dose will reduce the underlying risk of veno-occlusive disease (VOD). Metabolic studies indicated that the calicheamicin derivative is released hydrolytically from gemtuzumab ozogamicin. Many metabolites of this derivative were found in human liver microsomes and cytosol, and in HL-60 promyelocytic leukemia cells.

4.7.3.5. Possible side effects of gemtuzumab (Mylotarg)

Administration of gemtuzumab injection into the vein produces side reaction which again varies from patient to patient.

Following are the serious side effect may come during the course of treating with gemtuzumab :

• pain in your upper right stomach, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• swelling, rapid weight gain;
• feeling like you might pass out;
• pale skin, easy bruising or bleeding (such as nosebleeds), purple or red pinpoint spots under your skin;
• fever, chills, body aches, unusual weakness, flu symptoms;
• white patches or sores inside your mouth or on your lips;
• chest pain or tightness, feeling short of breath;
• lower back pain, blood in your urine;
• increased thirst, fruity breath odor, increased urination;
• urinating less than usual or not at all;
• numbness or tingly feeling around your mouth;
• muscle weakness, tightness, or contraction, overactive reflexes;
• fast or slow heart rate, weak pulse; or
• confusion, uneven heart rate, leg discomfort, muscle weakness or limp feeling.

Less serious side effects of administration of Mylotarg are:

• nausea, vomiting;
• diarrhea or constipation;
• headache;
• dizziness, anxiety, depressed mood; or
• sleep problems (insomnia).

4.7.3.6. Withdrawal of Mylotarg (gemtuzumab ozogamicin)

FDA notified healthcare professionals that results from a recent clinical trial raised new concerns about the product's safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Mylotarg (gemtuzumab ozogamicin) was approved in May 2000 under the FDA's accelerated approval program for treatment of acute myeloid leukemia (AML), a bone marrow cancer. A post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to know whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit i.e. survival time to acute myeloid leukemia patients. The trial was stopped early when no improvement in clinical benefit was observed. It was also found that a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. Therefore, it is now recommended that Mylotarg will not be commercially available to new patients.