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

Gestational Trophoblastic Disease

Gestational Trophoblastic Disease

Define: Abnormal pregnancy in which the developing fetus and placenta are replaced by proliferation of throphoblastic tissue.

¬  Spectrum of disease

a)      Benign  - Complete hydatidiform moles, partial mole

b)      Malignant – Invasive mole, Choriocarcinoma, placenta site trophoblastic tumor

Gestational trophoblastic Neoplasia

Define: any evidence of persistence of GTD with persistent elevation of beta human chorionic gonadotrophin

Differentiate

Complete Hydatidiform mole	Partial mole
46XX Homozygous (75-80%) -duplication of a single sperm following fertilisation of an ‘empty’ ovum 46XY Heterozygous (20-25%) -dispermic fertilisation of an ‘empty’ ovum	69XXY triploid (from maternal & paternal) - two sets of paternal haploid genes and one set of maternal haploid genes -following dispermic fertilisation of an ovum (10% are tetraploid or mosaic conception)
No embryonic or fetal tissue	embryonic or fetal tissue
Diffuse trophoblastic hyperplasia	Focal trophoblastic – variable changes
Generalized swelling of villous tissue -all hydrophic	Focal swelling of villous tissue -some hydrophic
May develop malingnant changes	Less likely to develop malignant changes

Symptoms and signs of molar pregnancy:

¬  classic features 

a)      irregular vaginal bleeding (Passing out “grape-like structure” )

b)      hyperemesis

c)      excessive uterine enlargement

d)      early failed pregnancy.

¬  Rarer presentations : hyperthyroidism, early onset pre-eclampsia or abdominal distension due to theca lutein cysts

¬  Very rarely: acute respiratory failure or neurological symptoms such as seizures (metastatic)

Diagnosis

¬  Ultrasound examination is helpful in making a pre-evacuation diagnosis.

¬  Definitive diagnosis is made by histological examination of the products of conception.

Investigation

¬  FBC, Coagulation profile

¬  Blood group cross match

¬   BhCG

In women with a complete mole, the quantitative serum beta-hCG level is higher than expected, often exceeding 100,000 IU/L. In case of a partial mole, the level of beta-hCG is often within the wide range associated with normal pregnancy and the symptoms are usually less pronounced. For these reasons the diagnosis of a partial mole is often missed clinically and made from subsequent histologic assessment of the abortive materia

¬  Ultrasound : ‘snow’storm’ appearance, no fetal parts seen, bilateral theca lutein cysts in POD

¬  Chest X-ray - exclude invasive mole in lung

Treatment

1.      Evacuation of molar pregnancy

a)      Complete molar pregnancies : Suction curettage.

b)      Partial molar pregnancies : Suction curettage  except when the size of the fetal parts deters the use of suction curettage, then medical evacuation can be used.

¬  Medical evacuation of complete molar pregnancies should be avoided because

-           the routine use of potent oxytocic agents lead to contraction of myometrium and potential to embolise and disseminate trophoblastic tissue through the venous system

-          Use of mifepristone and misoprostol increases the sensitivity of the uterus to prostaglandins

¬  Preparation of the cervix (to ripen it) immediately prior to evacuation is safe

-          Prolonged cervical preparation, particularly with prostaglandins, should be avoided  to reduce the risk of embolisation of trophoblastic cells.

2.      The use of oxytocic infusion prior to completion of the evacuation is not recommended.

¬  Excessive vaginal bleeding can be associated with molar pregnancy and a senior surgeon directly

supervising surgical evacuation is advised.

¬  If the woman had significant haemorrhage prior to evacuation, surgical evacuation should be expedited and the need for oxytocin infusion weighed up against the risk of tumour embolisation.

3.      Histologic assessment

¬  If obtained from the medical or surgical management of all failed pregnancies is recommended to exclude trophoblastic neoplasia.

¬  No need to routinely send products of conception for HPE after surgical termination of pregnancy, provided that fetal parts have been identified on prior ultrasound examination.

4.      A urinary pregnancy test should be performed 3 weeks after medical management of failed pregnancy if products of conception are not sent for histological examination.

5.      Anti-D prophylaxis is required following evacuation of a molar pregnancy (may delayed)

-          Required in partial mole

-          Not required in complete mole because of poor vascularisation of the chorionic villi and absence of the anti-D antigen

                                                                  

Women need investigated for GTN after non-molar pregnancy

¬  Any woman who develops persistent vaginal bleeding after a pregnancy event is at risk

¬  A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event.

¬  Symptoms from metastatic disease can occur very rarely.

Follow-up

The aims of follow-up are to confirm successful treatment and to identify women with persistent or malignant GTD who may require adjuvant chemotherapy or surgery at an early stage. Persistent vaginal bleeding and above all elevation of serum beta-hCG levels are the main indicators of residual disease.

The outcome of a partial hydatidiform mole after uterine evacuation is almost always benign. Persistent disease occurs in 1.2% to 4% of cases; metastasis occurs only in 0.1% of cases 

 In complete moles, these risks are approximately 5 times greater after treatment with uterine evacuation and 2-3 times greater after hysterectomy 

The risk of persistent or recurrent GTD is greatest in the first 12 months after evacuation, with most cases presenting within 6 months.

A variety of hCG criteria have been used to diagnose postmolar gestational trophoblastic disease. Recently, the International Federation of Gynecologists and Obstetricians (FIGO) standardized the following hCG criteria for the diagnosis of postmolar gestational trophoblastic disease

• An hCG level plateau of four values ±10% recorded over a 3-week duration (days 1, 7, 14, and 21).
• An hCG level increase of more than 10% of three values recorded over a 2-week duration (days 1, 7, and 14).
• Persistence of detectable hCG for more than 6 months after molar evacuation.

Use of reliable hormonal contraception is recommended while hCG values are being monitored. Oral contraceptives do not increase the incidence of postmolar gestational trophoblastic disease or alter the pattern of regression of hCG values 

Frequent pelvic examinations are performed while hCG values are elevated to monitor the involution of pelvic structures and to aid in the early identification of vaginal metastases. Although pregnancies after molar evacuation usually are normal gestations, pregnancy obscures the value of monitoring hCG levels during this interval and may result in a delayed diagnosis of postmolar malignant gestational trophoblastic disease. A new intrauterine pregnancy should be ruled out on the basis of hCG levels and ultrasonography, especially when there has been a long delay in follow-up of serial hCG levels and noncompliance with contraception. After completion of documented remission for 6-12 months, women who desire pregnancy may discontinue contraception, and hCG monitoring may be discontinued. 

Patients with prior partial or complete moles have a 10-fold increased risk (1-2% incidence) of a second hydatidiform mole in a subsequent pregnancy. 

Therefore, all future pregnancies should be evaluated by early obstetric ultrasonography.

Chemotherapy

Complete molar pregnancy is well recognized to have the potential for local invasion and distant spread. After evacuation, local uterine invasion occurs in about 15% and metastases in 4%. Complete molar pregnancy is usually divided into low and high risk for persistence based on signs and symptoms of marked trophoblastic proliferation at the time of evacuation, i.e.: hCG >100,000 mIU/Ml; excessive uterine enlargement; theca-lutein ovarian cyst >6 cm in diameter; older maternal age; a previous molar pregnancy. The risk of postmolar GTD is significant less with partial molar pregnancy and is seen in approximately 1-6%

Prognosis

Table 1. Gestational Trophoblastic Neoplasia (GTN)^a,b

FIGO Anatomical Staging
Stage
I	Disease confined to the uterus.
II	GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament).
III	GTN extends to the lungs, with or without known genital tract involvement.
IV	All other metastatic sites.
Modified WHO Prognostic Scoring System as Adapted by FIGOb
Scores	0	1	2	4
Age	<40	≥40	–	–
Antecedent pregnancy	mole	abortion	term	–
Interval months from index pregnancy	<4	4–6	7–12	>12
Pretreatment serum hCG (iu/1)	<103	103–104	104–105	>105
Largest tumor size (including uterus)	<3	3–4 cm	≥5 cm	–
Site of metastases	lung	spleen, kidney	gastrointestinal	liver, brain
Number of metastases	–	1–4	5–8	>8
Previous failed chemotherapy	–	–	single drug	≥2 drugs

  In this scoring system, women with a score of 7 or greater are considered at high risk.

Ref:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279094/ 

http://www.cancer.gov/cancertopics/pdq/treatment/gestationaltrophoblastic/HealthProfessional/page3

• May Allah Bless our job and our patients.
  -Amin-