Methyldopa

 

Manufacturer	Pharmaniaga Manufacturing Berhad
Distributor	Pharmaniaga Logistics
Contents	Methyldopa
Indications	Mild to moderate HTN.
Dosage	Adult Initially 250 mg daily for 2 days. May increase by 250 mg at 2-day intervals. Max: 2 g/day. Childn Initially 10 mg/kg bd-tds. Max: 65 mg/kg/day.
Administration	May be taken with or without food.
Contraindications	Phaeochromocytoma, depression, active hepatitis, hepatic or renal insufficiency.
Special Precautions	In halothane narcosis, risk of hepatotoxicity & intensity of narcosis may be enhanced.
Adverse Drug Reactions	Sedation, headache, weakness, dizziness, parkinsonism, bradycardia, orthostatic hypotension, GI symptoms, hepatic impairment, impotence. View ADR Monitoring Website
Drug Interactions	Other antihypertensives, anaesth, lithium. View more drug interactions with Pharmaniaga Methyldopa
Pregnancy Category (US FDA)	Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).
MIMS Class	Other Antihypertensives
ATC Classification	C02AB01 - methyldopa (levorotatory) ; Belongs to the class of methyldopa, centrally-acting antiadrenergic agents. Used in the treatment of hypertension.
Poison Schedule	B

Presentation/Packing

Form Photo Packing/Price Pharmaniaga Methyldopa film-coated tab 250 mg 50 × 10's (RM180.00/box)

 

 

Pharmacokinetics and Metabolism

The maximum decrease in blood pressure occurs four to six hours after oral dosage. Once an effective dosage level is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. After withdrawal, blood pressure usually returns to pretreatment levels within 24–48 hours.

Methyldopa is extensively metabolized. The known urinary metabolites are: α-Methyldopa mono-O-sulfate; 3-0-methyl-α-Methyldopa; 3,4-dihydroxyphenylacetone; α-Methyldopamine; 3-0-methyl-α-Methyldopamine and their conjugates.

Approximately 70 percent of the drug which is absorbed is excreted in the urine as Methyldopa and its mono-O-sulfate conjugate. The renal clearance is about 130 mL/min in normal subjects and is diminished in renal insufficiency. The plasma half-life of Methyldopa is 105 minutes. After oral doses, excretion is essentially complete in 36 hours.
Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.

Contraindications

Methyldopa is contraindicated in patients:

• with active hepatic disease, such as acute hepatitis and active cirrhosis.
• with liver disorders previously associated with Methyldopa therapy (see WARNINGS).
• with hypersensitivity to any component of this product.
• on therapy with monoamine oxidase (MAO) inhibitors.

Warnings

It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with Methyldopa therapy.

With prolonged Methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of Methyldopa therapy.
Lowest incidence is at daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications.

If a positive Coombs test develops during Methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem.

Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
If Coombs-positive hemolytic anemia occurs, the cause may be Methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered.


Should the need for transfusion arise in a patient receiving Methyldopa, both a direct and an indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.

Occasionally, fever has occurred within the first three weeks of Methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.

Precautions

General

Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction (see WARNINGS).

Some patients taking Methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
Hypertension has recurred occasionally after dialysis in patients given Methyldopa because the drug is removed by this procedure.
Rarely, involuntary choreoathetotic movements have been observed during therapy with Methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.

REF:
http://www.drugs.com/pro/methyldopa.html
http://www.mims.com/MALAYSIA/drug/info/Pharmaniaga%20Methyldopa/#Content

The ORACLE Children Study

Prematurity in babies

Every year, about one in eight babies, or 80,000 a year, are born prematurely (before 37 weeks) in the UK. Prematurity is the most common reason for babies to die in the first month after birth. Premature babies who survive are more likely to have short-term problems such as breathing and feeding difficulties and infections. They may also have longer-term problems with functioning, behaviour and learning. Whatever happens, having a premature baby is often a traumatic and upsetting experience for women and their families.

Research, like the ORACLE Trial and Children Study, to try to find the best ways to treat premature labour and reduce short and long term problems is very important.

Results of the original ORACLE Trial: women whose waters broke early

The antibiotic erythromycin seemed to be helpful for babies in the short-term. In the Erythromycin Group, babies were more likely to stay in the womb longer, and were less likely to need help with breathing, to have infections, or to have an abnormal brain scan.

The other antibiotic, co-amoxiclav, also increased the time babies stayed in the womb and reduced their need for oxygen. But the trial discovered an important problem with co-amoxiclav. There was a small increase in the number of babies born with a rare, sometimes very serious bowel condition called necrotising enterocolitis (NEC) to women with broken waters who were in the Co-amoxiclav Group. Because of its large size and design, the ORACLE trial was able to identify this rare risk, even though co-amoxiclav had previously been routinely used in pregnancy without reported problems.

 

Results of the original ORACLE Trial: women who had signs of going into labour early but didn’t have broken waters

The antibiotics used in the trial (erythromycin and co-amoxiclav) did not have any short-term effects (good or bad) for babies born to women with signs of early labour without broken waters.

What was measured in the ORACLE Children study

 

The questionnaire aimed to find out about children’s health, wellbeing and educational attainment. These are areas where there may sometimes be problems in any baby born early.

Functioning: The questionnaire asked about the child’s vision, hearing, speech, walking, dexterity (using their hands), emotions, pain, and aspects of thinking such as learning and remembering. Children were classed by researchers as having a ‘functioning’ difficulty if parents reported that children had any difficulties at all in any of these areas. As a result, ‘functioning’ difficulties can range from the child having minor difficulties (things like wearing glasses, requiring a hearing aid, not always being completely happy, or having some difficulty when trying to solve day to day problems), to more severe problems (such as being unable to walk, see, hear or speak, or having severe difficulties with thinking and remembering).

Health problems and behaviour: The questionnaire asked about chest symptoms, hospital admissions, fits/seizures, and specific medical conditions (including cerebral palsy), as well as behaviour, emotions, hyperactivity, and relationships with others.

Educational attainment: The National Curriculum (Key Stage 1) tests for reading, writing and maths, which are undertaken by children aged 7 in England, were used to assess how well the children were doing at school

Results of the ORACLE Children Study: women whose waters broke early

•    For mothers whose waters broke early, having antibiotics (erythromycin or co-amoxiclav) in the ORACLE trial did not make any difference to their child’s functioning, behaviour, most medical conditions, or Key Stage 1 results.

•    Parents were specifically asked about bowel problems because of the findings of the ORACLE trial (mentioned earlier). The Children Study found that in the Co-amoxiclav Group, there was a small increase in the number of children with bowel problems (2.7%) compared with those who were not given co-amoxiclav at all (1.6%). However, the bowel problems in children reported by these parents were mostly not serious (such as constipation).

There is, therefore, little evidence of long term effects (good or bad) for children of women who had antibiotics when their waters broke early, but there is a need for caution about use of co-amoxiclav in this situation.

 

Results of the ORACLE Children Study: women who had signs of going into labour early without broken waters.

•    For mothers who had signs of early labour without broken waters, having antibiotics (erythromycin or co-amoxiclav) did not make any difference to their child’s behaviour, most medical conditions, or Key Stage 1 results.

•           Functioning problems are common in children whose mothers showed signs of early labour without broken waters. It is normal for about 40% (4 in every 10) children born in this situation to have some kind of functioning problem. Being in the Co-amoxiclav Group did not make any difference to children’s functioning. However, in the Erythromycin Group, there were slightly more children with a ‘functioning’ problem compared with those whose mothers who did not have any erythromycin. These functioning problems included very mild difficulties (see “What was measured in the ORACLE Children Study” box), and most of the functioning problems reported by parents were minor

It was found that cerebral palsy in children was somewhat more common when women with signs of early labour did have antibiotics. In the Erythromycin Group, 3.3% of children had cerebral palsy compared with 1.7% of children whose mothers who did not have erythromycin. In the Co-amoxiclav Group, 3.2% of children had cerebral palsy compared with 1.9% of children whose mothers who did not have any co-amoxiclav 

Looking at it in more detail, the increase in the number of children with cerebral palsy was clearest in the group of women who had both antibiotics (co-amoxiclav and erythromycin together). In this group, 4.4% of children had cerebral palsy, though even here the numbers with cerebral palsy remain quite small.

Summary

The ORACLE trial has shown that the babies of women who had PPROM and received erythromycin had an improved outcome compared to those who did not have PPROM, including increasing the time to delivery, reduction of infection and improved respiratory function. The ORACLE Children Study however revealed that these early improved outcomes do not make a substantial difference to the children’s health and development long-term.
However, in those women who did not have PPROM, the study suggested that there may be a small increased risk of functional impairment and cerebral palsy in the children of women who took antibiotics because of early premature labour.
These findings do not mean that antibiotics are unsafe for use in pregnancy. Pregnant women showing signs of infection should be treated promptly with antibiotics

Ref:

http://www.le.ac.uk/oraclechildren 

http://www.rcog.org.uk/what-we-do/campaigning-and-opinions/statement/rcog-statement-oracle-children-study

http://www.rcog.org.uk/womens-health/clinical-guidance/preterm-prelabour-rupture-membranes-green-top-44

http://www.rcog.org.uk/womens-health/clinical-guidance/prevention-early-onset-neonatal-group-b-streptococcal-disease-green-