"Adverse Drug Event "

Possible Phenobarbitone induced Megaloblastic Anemia

Case report:
A 22 year old female patient was admitted to the department of medicine of our institute with complaints of easy fatiguability, vomiting and pedal edema since one month. Patient was a diagnosed case of generalized tonic clonic seizure disorder since last 10 years, well controlled on Tab. Phenobarbitone (60mg twice daily) and Tab. Carbamazepine (400mg twice daily). Patient was also taking Tab. Clobazam (10mg once daily) since June 2005.

Investigations on the day of admission (Day1) revealed Hb-3.8 gm % (Normal: 12-16gm %), Total Leucocyte Count (TLC)-2700/mm³ (Normal: 4000-11,000/mm³) and platelets-100000/mm³ (Normal: 150000-350000/mm³). On Day 2, bone marrow examination revealed Hb-4.3gm%, Packed Cell Volume (PCV)- 10.5% (Normal: 36-48%), mean corpuscular volume (MCV)-107.3fl (Normal:78-102fl), mean corpuscular hemoglobin concentration (MCHC) - 40.1g/dl (Normal:31-37g/dl), Red Cell Distribution Width (RDW)-19.6% (Normal:11.5-14.5%), anisocytosis (++), macrocytosis (++), microcytosis (++), hypochromasia (+), poikilocytosis (++), micro-ovalocytes (+), target cell/ tear drop cell (++),basophilic stippling (+). Patient was diagnosed as a case of megaloblastic anemia. He was started with Tab Folic acid (5mg twice daily) along with Tab. Ferrous hydroxide, Inj.multivitamin in 100 ml normal saline over one hour intravenously once a day. In addition, urine examination showed albuminuria with 10-12 leucocytes and a field full of bacteria; E-coli was grown that was sensitive to Amikacin. The Hematologist advised continuation of multivitamin and folic acid.

On Days 3 and 4 patient was transfused with 2 units of whole blood and cap. Doxycycline (100mg once daily) was added to above treatment. On Day 5, investigations revealed Hb-5.4 gm%, TLC-4400/ mm³, platelets-60,000/ mm³.On Day 6 patient was transfused with another unit of whole blood and Inj.Amikacin (500mg Intravenous once a day) was started. On Day 7, patient's Hb was 6.8gm%, clinical features began resolving and patient was discharged. Prior to admission patient was not taking folic acid, which was started on Day 1 after diagnosis of severe anemia. Patient responded well to folic acid given over a period of 6 days along with 3 units of whole blood transfusion, and Inj.multivitamin. Considering the possibility of drug induced megaloblastic anemia Phenobarbitone was tapered and patient was advised to continue Tab.folic acid 5mg twice daily along with multivitamins and Tab.Carbamazepine (400mg twice daily) and Tab.Clobazam (10mg once a day).

Discussion
Megaloblastic anemia is caused by deficiency of folic acid and vitamin B12.[1] It can be designated drug-induced only after exclusion of other recognized causes. Phenobarbitone is an effective agent for generalized tonic-clonic and partial seizures. Its efficacy, low toxicity and low cost make it an important agent for these types of epilepsy. The development of megaloblastic anemia during the use of barbiturates as anticonvulsants probably depends on dosage. The usual maximal daily dose of phenobarbitone used is 200mg. Clinically significant untoward effects occur during long term use by impairing absorption of folic acid in the proximal part of small intestine.[2] Our patient had taken 120 mg daily for the last 10 years before she developed, insidious onset megaloblastic anemia. Phenobarbitone also interferes particularly with pteroylpolyglutamate synthesis in liver. This is proved by lower polyglutamate content, lower 3H folate incorporation in polyglutamate forms and in protein-bound folates, lower blood radioactivity, higher urinary excretion of 3H folate metabolites and by higher 3H folate concentration in kidneys.

In the present case, the likely explanation could be that phenobarbitone interfered with folic acid metabolism. It might have also impaired folic acid absorption at the level of proximal part of small intestine. But since folic acid levels were not done in this patient, dietary deficiency can be attributed to have caused megaloblastic anemia. There is little evidence that dietary deficiency of folic acid per se causes severe megaloblastic anemia. The work done by Forshaw et al. states that a poor diet precedes the development of megaloblastic anemia associated with anticonvulsant therapy.[3] Therapeutically, folic acid is the drug of choice for the treatment of megaloblastic anemia.

As per Naranjo's algorithm scale, score for causality analysis was 3 and phenobarbitone was found to be the 'possible' cause [4]. Diet rich in folic acid like orange juice, green leafy vegetables, soyabeans, along with folic acid supplements are advisable in a patient on long term treatment with antiepileptic drugs.

Summary
A 22-year-old female presented with a severe megaloblastic anemia after treatment of her epilepsy for ten years with phenobarbitone 120mg daily, and in therapeutic dose. This drug possibly appears to have caused the megaloblastic anemia, either alone or in combination with dietary deficiency. After supplementation of folic acid, hematologic remission was observed.

References
1. Girdwood RH. The megaloblastic anaemias; their investigation and classification. Q J Med. 1956 Jan; 25(97):87-119.

2. Iivanainen M, Savolainen H. Side effects of Phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Supplement. 1983; 97:49-67.

3. Forshaw J WB. Megaloblastic anaemia associated with anticonvulsant therapy. Postgrad Med J. 1957; 33:242.

4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA , Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reaction. Clin Pharmacol Ther. 1981; 8:239 - 44.