Methyldopa and hydrochlorothiazide

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For methyldopa and hydrochlorothiazide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to methyldopa and hydrochlorothiazide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Although there is no specific information comparing use of methyldopa and hydrochlorothiazide in children with use in other age groups, it is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

Dizziness or light-headedness, drowsiness, or signs of too much potassium loss may be more likely to occur in the elderly, who are more sensitive to the effects of methyldopa and hydrochlorothiazide.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking methyldopa and hydrochlorothiazide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using methyldopa and hydrochlorothiazide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Brofaromine
• Clorgyline
• Dofetilide
• Furazolidone
• Iproniazid
• Isocarboxazid
• Lazabemide
• Linezolid
• Moclobemide
• Nialamide
• Pargyline
• Phenelzine
• Procarbazine
• Rasagiline
• Selegiline
• Toloxatone
• Tranylcypromine

Using methyldopa and hydrochlorothiazide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Acetyldigoxin
• Amphetamine
• Amtolmetin Guacil
• Arsenic Trioxide
• Aspirin
• Benzphetamine
• Bromfenac
• Bufexamac
• Celecoxib
• Choline Salicylate
• Clonixin
• Cyclophosphamide
• Deslanoside
• Dexibuprofen
• Dexketoprofen
• Dextroamphetamine
• Diclofenac
• Diflunisal
• Digitalis
• Digitoxin
• Digoxin
• Dipyrone
• Droperidol
• Droxicam
• Entacapone
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Flecainide
• Floctafenine
• Flufenamic Acid
• Flurbiprofen
• Ibuprofen
• Indomethacin
• Ketanserin
• Ketoprofen
• Ketorolac
• Levomethadyl
• Lisdexamfetamine
• Lithium
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Methamphetamine
• Methotrexate
• Metildigoxin
• Morniflumate
• Nabumetone
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Ouabain
• Oxaprozin
• Oxyphenbutazone
• Parecoxib
• Phenylbutazone
• Piketoprofen
• Piroxicam
• Proglumetacin
• Propyphenazone
• Proquazone
• Proscillaridin
• Pseudoephedrine
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sodium Salicylate
• Sotalol
• Sulindac
• Tenoxicam
• Tiaprofenic Acid
• Tolfenamic Acid
• Tolmetin
• Valdecoxib

Using methyldopa and hydrochlorothiazide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alprenolol
• Aminolevulinic Acid
• Bepridil
• Bisoprolol
• Carbamazepine
• Cholestyramine
• Ferric Ammonium Citrate
• Ginkgo
• Gossypol
• Haloperidol
• Iron
• Licorice
• Phenylpropanolamine
• Sotalol
• Timolol
• Topiramate

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of methyldopa and hydrochlorothiazide. Make sure you tell your doctor if you have any other medical problems, especially:

• Angina (chest pain)—Methyldopa may worsen the condition.

• Type 2 diabetes mellitus—Hydrochlorothiazide may change the amount of diabetes medicine needed.

• Gout (history of)—Hydrochlorothiazide may increase the amount of uric acid in the blood, which can lead to gout.

• High cholesterol—Hydrochlorothiazide may raise cholesterol levels.

• Kidney disease—Effects of methyldopa and hydrochlorothiazide may be increased because of slower removal from the body. If severe, hydrochlorothiazide may not work.

• Liver disease—Effects of methyldopa may be increased because of slower removal from the body. If hydrochlorothiazide causes loss of too much water from the body, liver disease can become much worse.

• Lupus erythematosus (history of)—Hydrochlorothiazide may worsen the condition.

• Mental depression (history of)—Methyldopa can cause mental depression
• Pancreatitis (inflammation of the pancreas)
• Parkinson's disease—Methyldopa may worsen the condition.
• Pheochromocytoma—Methyldopa may interfere with tests for the condition. In addition, there have been reports of increased blood pressure.

In addition to the use of the medicine your doctor has prescribed, appropriate treatment for your high blood pressure may include weight control and care in the types of foods you eat, especially foods high in sodium. Your doctor will tell you which factors are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that methyldopa and hydrochlorothiazide will not cure your high blood pressure but it does help control it. Therefore, you must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

methyldopa and hydrochlorothiazide may cause you to have an unusual feeling of tiredness when you begin to take it. You may also notice an increase in the amount of urine or in your frequency of urination. After taking the medicine for a while, these effects should lessen. In general, to keep the increase in urine from affecting your sleep:

• If you are to take a single dose a day, take it in the morning after breakfast.
• If you are to take more than one dose a day, take the last dose no later than 6 p.m., unless otherwise directed by your doctor.

However, it is best to plan your dose or doses according to a schedule that will least affect your personal activities and sleep. Ask your health care professional to help you plan the best time to take methyldopa and hydrochlorothiazide.

To help you remember to take your medicine, try to get into the habit of taking it at the same time each day.

Dosing

The dose of methyldopa and hydrochlorothiazide will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of methyldopa and hydrochlorothiazide. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For treating high blood pressure:
  • For oral dosage form (tablets):
    • Adults: Two to four tablets a day, taken as a single dose or in divided doses.
    • Children: Dose must be determined by your doctor.

Missed Dose

If you miss a dose of methyldopa and hydrochlorothiazide, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take methyldopa and hydrochlorothiazide or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to methyldopa and hydrochlorothiazide. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

This fixed combination product combines two antihypertensives: Methyldopa and Hydrochlorothiazide.

Methyldopa

Methyldopa is an antihypertensive and is the L-isomer of alpha-methyldopa. It is levo-3-(3,4-Dihydroxy-phenyl)-2-methylalanine sesquihydrate. Its molecular formula is C10H13NO4•1 ½ H2O with a molecular weight of 238.24, and its structural formula is:

Methyldopa is a white to yellowish white, odorless fine powder and is sparingly soluble in water.

Hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7H8CIN3O4S2 and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.75 which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Each tablet for oral administration contains:

250 mg methyldopa and 15 mg
hydrochlorothiazide,
or
250 mg methyldopa and 25 mg
hydrochlorothiazide.

Potency for methyldopa is calculated on anhydrous basis. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin.

Methyldopa

Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.

Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.

Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.

Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.

Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Hydrochlorothiazide

The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.

Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

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 to 48 hours.

Methyldopa is extensively metabolized. The known urinary metabolites are: α- methyldopa mono-O-sulfate; 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenyl acetone; α-methyldopamine; 3-O-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.

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

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.

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially after prolonged therapy or when severe cirrhosis is present (see CONTRAINDICATIONS and WARNINGS).

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium sparing diuretics or potassium supplements such as foods with a high potassium content.

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.

In diabetic patients dosage adjustment of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Laboratory Tests

Blood count, Coombs test and liver function tests, are recommended before initiating therapy and at periodic intervals (see WARNINGS).

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.

Drug Interactions

When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.

Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.

Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS.

When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the prescribing information for lithium preparations.

Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or gluconate is not recommended.

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs: (Oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs: Additive effect or potentiation.

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.

Lithium: Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Methyldopa and Hydrochlorothiazide.

Nonsteroidal Anti-inflammatory Drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Methyldopa and Hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Drug/Laboratory Test Interactions

Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported.

Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of the combination.

No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).

Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatid exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.

Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vitro in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation.

Pregnancy

Use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Pregnancy Category C

Animal reproduction studies have not been conducted with Methyldopa and Hydrochlorothiazide. It is also not known whether Methyldopa and Hydrochlorothiazide can affect reproduction capacity or can cause fetal harm when given to a pregnant woman. Methyldopa and Hydrochlorothiazide should be given to a pregnant woman only if clearly needed.

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women.

Reproduction studies performed with methyldopa at oral doses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealed no evidence of harm to the fetus. These doses are 16.6 times, 3.3 times and 1.7 times, respectively, the maximum daily human dose when compared on the basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg. There are however, no adequate and well-controlled studies in pregnant women in the first trimester of pregnancy. Because animal reproduction studies are not always predictive of human response, methyldopa should be used during pregnancy only if clearly needed.

Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of fetal harm appears remote. In five studies, three of which were controlled, involving 332 pregnant hypertensive women, treatment with methyldopa was associated with an improved fetal outcome. The majority of these women were in the third trimester when methyldopa therapy was begun.

In one study, women who had begun methyldopa treatment between weeks 16 and 20 of pregnancy gave birth to infants whose average head circumference was reduced by a small amount (34.2 ± 1.7 cm vs. 34.6 ± 1.3 cm [mean ± 1 S.D.]). Long-term follow-up of 195 (97.5%) of the children born to methyldopa-treated pregnant women (including those who began treatment between weeks 16 and 20) failed to uncover any significant adverse effect on the children. At four years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers were treated with methyldopa during pregnancy than those whose mothers were untreated. The children of the treated group scored consistently higher than the children of the untreated group on five major indices of intellectual and motor development. At age 7 and one-half developmental scores and intelligence indices showed no significant differences in children of treated or untreated hypertensive women.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in adults.

Nursing Mothers

Methyldopa and thiazides appear in breast milk. Therefore, because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Methyldopa and Hydrochlorothiazide in pediatric patients has not been established.

Geriatric Use

Clinical studies of Methyldopa and Hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Methyldopa and Hydrochlorothiazide Tablets, USP are available as follows:

The 250 mg/15 mg tablets are green, round, unscored, film-coated tablets debossed with MYLAN on one side and 507 on the other side. They are available as follows:

NDC 0378-0507-01
bottles of 100 tablets

The 250 mg/25 mg tablets are green, capsule-shaped, unscored, film-coated tablets debossed with MYLAN on one side and 711 on the other side. They are available as follows:

NDC 0378-0711-01
bottles of 100 tablets

NDC 0378-0711-10
bottles of 1000 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

REVISED NOVEMBER 2005

MDHZ:R5AQ

ACE Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Allopurinol: Thiazide and Thiazide-Like Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Analgesics (Opioid): May enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benazepril: HydroCHLOROthiazide may enhance the hypotensive effect of Benazepril. HydroCHLOROthiazide may enhance the nephrotoxic effect of Benazepril. Benazepril may decrease the serum concentration of HydroCHLOROthiazide. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification

Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Monitor therapy

CarBAMazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

COMT Inhibitors: May decrease the metabolism of COMT Substrates. Monitor therapy

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Monitor therapy

Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dofetilide: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Iobenguane I 123: Methyldopa may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ipragliflozin: May enhance the adverse/toxic effect of Thiazide and Thiazide-Like Diuretics. Specifically, the risk for intravascular volume depletion may be increased. Monitor therapy

Iron Salts: May decrease the serum concentration of Methyldopa. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Avoid combination

Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Methyldopa. Avoid combination

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Methyldopa. Management: Consider separating doses of these products by 2 or more hours to minimize this interaction; however, the success of this action appears limited. Monitor for decreased therapeutic effects of methyldopa with concurrent use. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

OXcarbazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Promazine: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Promazine. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Consider therapy modification

Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Monitor therapy

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Consider therapy modification

Valsartan: HydroCHLOROthiazide may enhance the hypotensive effect of Valsartan. Valsartan may increase the serum concentration of HydroCHLOROthiazide. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

See individual agents.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, constipation, diarrhea, fatigue, nausea, vomiting, lack of appetite, or loss of strength and energy. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea, or vomiting), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), severe dizziness, passing out, bruising, bleeding, chills, pharyngitis, angina, abnormal movements, burning or numbness feeling, shortness of breath, excessive weight gain, swelling of arms or legs, bradycardia, nightmares, agitation, vision changes, or eye pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.