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NDC 00378-0445-01 Metoprolol Tartrate and Hydrochlorothiazide 50; 100 mg/1; mg/1 Details
Metoprolol Tartrate and Hydrochlorothiazide 50; 100 mg/1; mg/1
Metoprolol Tartrate and Hydrochlorothiazide is a ORAL TABLET in the HUMAN PRESCRIPTION DRUG category. It is labeled and distributed by Mylan Pharmaceuticals Inc.. The primary component is HYDROCHLOROTHIAZIDE; METOPROLOL TARTRATE.
MedlinePlus Drug Summary
Hydrochlorothiazide is used alone or in combination with other medications to treat high blood pressure. Hydrochlorothiazide is used to treat edema (fluid retention; excess fluid held in body tissues) caused by various medical problems, including heart, kidney, and liver disease and to treat edema caused by using certain medications including estrogen and corticosteroids. Hydrochlorothiazide is in a class of medications called diuretics ('water pills'). It works by causing the kidneys to get rid of unneeded water and salt from the body into the urine. High blood pressure is a common condition and when not treated, can cause damage to the brain, heart, blood vessels, kidneys and other parts of the body. Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems. In addition to taking medication, making lifestyle changes will also help to control your blood pressure. These changes include eating a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 minutes most days, not smoking, and using alcohol in moderation.
Related Packages: 00378-0445-01Last Updated: 11/30/2022
MedLinePlus Full Drug Details: Hydrochlorothiazide
Metoprolol is used alone or in combination with other medications to treat high blood pressure. It also is used to prevent angina (chest pain) and to improve survival after a heart attack. Metoprolol also is used in combination with other medications to treat heart failure. Metoprolol is in a class of medications called beta blockers. It works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure. High blood pressure is a common condition and when not treated, can cause damage to the brain, heart, blood vessels, kidneys and other parts of the body. Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems. In addition to taking medication, making lifestyle changes will also help to control your blood pressure. These changes include eating a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 minutes most days, not smoking, and using alcohol in moderation.
Related Packages: 00378-0445-01Last Updated: 11/30/2022
MedLinePlus Full Drug Details: Metoprolol
Product Information
| NDC | 00378-0445 |
|---|---|
| Product ID | 0378-0445_30a7e036-f161-4393-a646-beeacc72e1f0 |
| Associated GPIs | 36992002200325 |
| GCN Sequence Number | 000414 |
| GCN Sequence Number Description | metoprolol/hydrochlorothiazide TABLET 100MG-50MG ORAL |
| HIC3 | J7H |
| HIC3 Description | BETA-BLOCKERS AND THIAZIDE,THIAZIDE-LIKE DIURETICS |
| GCN | 51552 |
| HICL Sequence Number | 000143 |
| HICL Sequence Number Description | METOPROLOL TARTRATE/HYDROCHLOROTHIAZIDE |
| Brand/Generic | Generic |
| Proprietary Name | Metoprolol Tartrate and Hydrochlorothiazide |
| Proprietary Name Suffix | n/a |
| Non-Proprietary Name | metoprolol tartrate and hydrochlorothiazide |
| Product Type | HUMAN PRESCRIPTION DRUG |
| Dosage Form | TABLET |
| Route | ORAL |
| Active Ingredient Strength | 50; 100 |
| Active Ingredient Units | mg/1; mg/1 |
| Substance Name | HYDROCHLOROTHIAZIDE; METOPROLOL TARTRATE |
| Labeler Name | Mylan Pharmaceuticals Inc. |
| Pharmaceutical Class | Adrenergic beta-Antagonists [MoA], Increased Diuresis [PE], Thiazide Diuretic [EPC], Thiazides [CS], beta-Adrenergic Blocker [EPC] |
| DEA Schedule | n/a |
| Marketing Category | ANDA |
| Application Number | ANDA076792 |
| Listing Certified Through | 2024-12-31 |
Package
Package Images
NDC 00378-0445-01 (00378044501)
| NDC Package Code | 0378-0445-01 |
|---|---|
| Billing NDC | 00378044501 |
| Package | 100 TABLET in 1 BOTTLE, PLASTIC (0378-0445-01) |
| Marketing Start Date | 2004-08-20 |
| NDC Exclude Flag | N |
| Pricing Information | N/A |
Standard Product Labeling (SPL)/Prescribing Information SPL b6cf0f43-8dc3-4535-b651-daf1f9e0336c Details
HIGHLIGHTS OF PRESCRIBING INFORMATION
METOPROLOL TARTRATE and HYDROCHLOROTHIAZIDE tablets, for oral use
Initial U.S. Approval: 1984
INDICATIONS AND USAGE
Metoprolol tartrate and hydrochlorothiazide is the combination tablet of metoprolol tartrate, a beta adrenoceptor blocker and hydrochlorothiazide (HCTZ), a thiazide diuretic, indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1)
DOSAGE AND ADMINISTRATION
- •
- Usual dose range: Hydrochlorothiazide 12.5 to 25 mg and metoprolol tartrate 100 mg dosed once daily. (2.1)
DOSAGE FORMS AND STRENGTHS
Tablets (metoprolol tartrate/hydrochlorothiazide: 50/25mg; 100/25mg; 100/50mg (3)
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
- •
- Abrupt cessation may exacerbate myocardial ischemia. (5.1)
- •
- May worsen congestive heart failure. (5.2)
- •
- Bronchospasm: Avoid beta-blockers. (5.3)
- •
- Bradycardia. (5.4)
- •
- Avoid discontinuing therapy prior to major surgery. (5.5)
- •
- May mask symptoms of hypoglycemia. (5.6)
- •
- Monitor serum electrolytes and creatinine periodically. (5.7)
- •
- Peripheral vascular disease: Can aggravate symptoms of arterial insufficiency. (5.9)
- •
- Pheochromocytoma: First initiate therapy with an alpha blocker. (5.10)
- •
- Abrupt withdrawal in thyrotoxicosis might precipitate a thyroid storm. (5.11)
- •
- Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. (5.12)
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
- •
- Catecholamine-depleting drugs (e.g., MAO inhibitors): Hypotension, bradycardia. (7.1)
- •
- CYP2D6 inhibitors: Increased metoprolol concentration. (12.3)
- •
- Digitalis glycosides, clonidine, diltiazem and verapamil: Bradycardia. (5.4, 7.1)
- •
- Clonidine: Rebound hypertension following clonidine withdrawal. (7.1)
- •
- Antidiabetic drugs: Dosage adjustment may be required. (7.2)
- •
- Cholestyramine and colestipol: Reduced absorption of thiazides. (7.2)
- •
- Lithium: Risk of lithium toxicity. (7.2)
- •
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects of diuretics. (7.2)
USE IN SPECIFIC POPULATIONS
- •
- Hepatic Impairment: Consider initiating metoprolol tartrate therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. (8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2022
Table Of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Abrupt Cessation of Therapy
5.2 Heart Failure
5.3 Bronchospastic Disease
5.4 Bradycardia
5.5 Major Surgery
5.6 Masked Symptoms of Hypoglycemia
5.7 Electrolyte and Metabolic Effects
5.8 Renal Impairment
5.9 Peripheral Vascular Disease
5.10 Pheochromocytoma
5.11 Thyrotoxicosis
5.12 Anaphylactic Reaction
5.13 Acute Myopia and Second Angle-Closure Glaucoma
5.14 Exacerbation of Systemic Lupus Erythematosus
6 ADVERSE REACTIONS
6.2 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Drug Interactions with Metoprolol
7.2 Drug Interactions with Hydrochlorothiazide
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
10.1 Signs and Symptoms
10.2 Management
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.5 Pharmacogenomics
13 NONCLINICAL TOXICOLOGY
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
- *
- Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE
Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Metoprolol tartrate and hydrochlorothiazide tablets may be administered with other antihypertensive agents.
Limitation of Use: Metoprolol tartrate and hydrochlorothiazide tablets are not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient’s needs, therapy with the fixed combination may be more convenient than with the separate components.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Titrate doses of individual components before switching to metoprolol tartrate and hydrochlorothiazide tablets.
Administer metoprolol tartrate and hydrochlorothiazide tablets with or immediately following meals.
Hydrochlorothiazide is usually given at a dosage of 12.5 mg to 50 mg per day. The usual initial dosage of metoprolol is 100 mg daily in single or divided doses. Dosage may be increased gradually until optimum blood pressure control is achieved.
Once daily dosing may not maintain the full effect for the entire dosing period, particularly at lower doses. In such patients, consider administration in divided doses.
Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended.
3 DOSAGE FORMS AND STRENGTHS
Metoprolol Tartrate and Hydrochlorothiazide Tablets, USP are available containing 50 mg or 100 mg of metoprolol tartrate, USP and 25 mg or 50 mg of hydrochlorothiazide, USP providing for the following available combinations: 50 mg/25 mg, 100 mg/25 mg or 100 mg/50 mg.
- •
- The 50 mg/25 mg tablets are peach, round, scored tablets debossed with M above the score and 424 below the score on one side of the tablet and blank on the other side.
- •
- The 100 mg/25 mg tablets are peach, oval, scored tablets debossed with M to the left of the score and 434 to the right of the score on one side of the tablet and blank on the other side.
- •
- The 100 mg/50 mg tablets are peach, capsule-shaped, scored tablets debossed with M to the left of the score and 445 to the right of the score on one side of the tablet and blank on the other side.
4 CONTRAINDICATIONS
Metoprolol tartrate and hydrochlorothiazide tablets are contraindicated in patients with:
- •
- Cardiogenic shock or decompensated heart failure.
- •
- Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place.
- •
- Anuria
- •
- Hypersensitivity to metoprolol tartrate or hydrochlorothiazide or to other sulfonamide-derived drugs.
5 WARNINGS AND PRECAUTIONS
5.1 Abrupt Cessation of Therapy
Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered metoprolol tartrate and hydrochlorothiazide tablets, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly resume therapy and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol tartrate in patients treated only for hypertension.
5.2 Heart Failure
Worsening cardiac failure may occur during up-titration of beta-blockers. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol. It may be necessary to lower the dose of metoprolol tartrate or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol tartrate.
5.3 Bronchospastic Disease
Beta adrenergic blockers can cause bronchospasm. Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta1 cardio-selectivity, however, metoprolol tartrate may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol tartrate and have bronchodilators (e.g., beta2-agonists) readily available or administered concomitantly.
5.4 Bradycardia
Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol tartrate and hydrochlorothiazide tablets. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff-Parkinson-White) or on concomitant drugs [see Drug Interactions (7)] that cause bradycardia may be at increased risk. Monitor heart rate in patients receiving metoprolol tartrate and hydrochlorothiazide tablets. If severe bradycardia develops, reduce or stop metoprolol tartrate and hydrochlorothiazide tablets.
5.5 Major Surgery
Avoid initiation of high-dose regimen of metoprolol tartrate and hydrochlorothiazide tablets in patients with cardiovascular risk factors undergoing non-cardiac surgery, since use in such patients has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta adrenergic blockers should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures [see Warnings and Precautions (5.1)].
5.6 Masked Symptoms of Hypoglycemia
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
5.7 Electrolyte and Metabolic Effects
Metoprolol tartrate and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide reduces clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.
5.8 Renal Impairment
Patients with chronic kidney disease, severe heart failure, or volume depletion may be at increased risk for developing acute renal failure on drugs containing hydrochlorothiazide, including metoprolol tartrate and hydrochlorothiazide tablets.
5.9 Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
5.10 Pheochromocytoma
If metoprolol tartrate and hydrochlorothiazide tablets are used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
5.11 Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
5.12 Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
5.13 Acute Myopia and Second Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause acute transient myopia and acute angle-closure glaucoma (idiosyncratic reactions). Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of hydrochlorothiazide initiation. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. Given that metoprolol tartrate and hydrochlorothiazide tablets contain hydrochlorothiazide, if these symptoms occur, discontinue metoprolol tartrate and hydrochlorothiazide tablets. Consider prompt medical or surgical treatment if the intraocular pressure remains uncontrolled.
6 ADVERSE REACTIONS
The following adverse reactions are described in more detail elsewhere in the label;
- •
- Worsening angina or myocardial infarction [see Warnings and Precautions (5)]
- •
- Worsening heart failure [see Warnings and Precautions (5)]
- •
- Worsening AV block [see Contraindications (4)]
6.2 Post-Marketing Experience
The following adverse reactions have been reported in postmarketing experience: adverse reactions have been identified during post approval use of metoprolol tartrate and hydrochlorothiazide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Metoprolol
Confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.
Hydrochlorothiazide
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).
Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, hyperuricemia.
Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.
Other Beta-Adrenergic Agent Reactions
A variety of adverse reactions have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol tartrate.
Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm and respiratory distress.
7 DRUG INTERACTIONS
7.1 Drug Interactions with Metoprolol
Catecholamine Depleting Drugs
The concomitant use of catecholamine-depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) with beta adrenergic blockers may have an additive affect and increase the risk of hypotension or bradycardia
CYP2D6 Inhibitors
Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology (12.3)]. Monitor patients closely when the combination cannot be avoided.
Digitalis, Clonidine, and Calcium Channel Blockers
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the betablocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped.
7.2 Drug Interactions with Hydrochlorothiazide
Antidiabetic Drugs (oral agents and insulin)
Dosage adjustment of the antidiabetic drug may be required.
Ion Exchange 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%, respectively. Stagger the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine and colestipol resins) such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins to minimize the interaction.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Untreated hypertension during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations). Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality with maternal use of beta blockers, including metoprolol, during pregnancy (see Data). There have been rare reports of jaundice, thrombocytopenia, and electrolyte imbalances in infants exposed to thiazide medications during pregnancy.
In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages up to 24 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. The combination of metoprolol tartrate/hydrochlorothiazide administered to rats from mid-late gestation through lactation also produced increased post-implantation loss and decreased neonatal survival (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Consideration
Disease-Associated Maternal and/or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions
Metoprolol
Metoprolol crosses the placenta. Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly.
Data
Human Data
Data from published observational studies did not demonstrate an association of major congenital malformations and use of either metoprolol or hydrochlorothiazide in pregnancy. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother. These observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy.
Animal Data
Oral administration of metoprolol tartrate/hydrochlorothiazide combinations to pregnant rats during organogenesis at doses up to 200/50 mg/kg/day (10 and 20 times the MRHD on a mg/m2 basis for metoprolol and hydrochlorothiazide, respectively) or to pregnant rabbits at doses up to 25/6.25 mg/kg/day (about 2.5 and 5 times the MRHD on a mg/m2 basis for metoprolol and hydrochlorothiazide, respectively) produced no teratogenic effects. A 200/50 mg/kg/day metoprolol tartrate/hydrochlorothiazide combination administered to rats from mid-late gestation through lactation produced increased post-implantation loss and decreased neonatal survival.
Metoprolol
Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 24 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity.
Hydrochlorothiazide
Hydrochlorothiazide administered to pregnant mice and rats during organogenesis at doses up to 3000 and 1000 mg/kg/day (600 and 400 times the MRHD on a mg/m2 basis), respectively, produced no harm to the fetus. Thiazides cross the placental barrier and appear in the cord blood.
8.2 Lactation
Risk Summary
There are no data on the presence of metoprolol tartrate and hydrochlorothiazide in human milk, the effects on the breastfed infant, or the effects on milk production. However, data are available on the individual components of metoprolol tartrate and hydrochlorothiazide tablets. Available data from published literature on metoprolol and hydrochlorothiazide report that each drug is present in human milk (see Data). There are no reports of adverse effects on breastfed infants exposed to metoprolol or hydrochlorothiazide during lactation. Doses of hydrochlorothiazide associated with clinically significant diuresis have been associated with impaired milk production. There is no information regarding the effects of metoprolol on milk production. Monitor infants exposed to metoprolol tartrate and hydrochlorothiazide tablets though breastmilk for drowsiness or poor feeding (see Clinical Considerations).
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metoprolol tartrate and hydrochlorothiazide tablets and any potential adverse effects on the breastfed child from metoprolol tartrate and hydrochlorothiazide tablets or from the underlying maternal condition.
Data
Metoprolol
Based on published case reports, the estimated daily infant dose of metoprolol received from breastmilk ranged from 0.05 mg to less than 1 mg. The estimated relative infant dosage was 0.5% to 2% of the mother’s weight-adjusted dosage.
In two women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. The estimated amount of metoprolol and alpha-hydroxymetoprolol in breast milk is reported to be less than 2% of the mother's weight-adjusted dosage.
In a small study, breast milk was collected every 2 to 3 hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage.
8.3 Females and Males of Reproductive Potential
Infertility
Males
Based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. No evidence of impaired fertility due to metoprolol or hydrochlorothiazide was observed in rats [see Nonclinical Toxicology (13)].
8.5 Geriatric Use
Clinical studies of metoprolol tartrate and hydrochlorothiazide tablets 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. Hydrochlorothiazide 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 [see Warnings and Precautions (5.8)]. 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 concomitant disease or other drug therapy.
10 OVERDOSAGE
10.1 Signs and Symptoms
The most frequently observed signs expected with overdosage of a beta adrenergic blocker are bradycardia and bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances and bronchospasm, atrioventricular block, hypoxia, impairment of consciousness/coma, cardiogenic shock, nausea and vomiting.
With thiazide diuretics, acute intoxication is rare. The most prominent feature of overdose is acute loss of fluid, electrolytes and magnesium. Signs and symptoms of overdose may include hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation/ impairment of consciousness.
Altered laboratory findings can also occur (e.g., hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, increased BUN).
10.2 Management
Care should be provided at a facility that can provide appropriate supporting measures, monitoring and supervision as treatment is symptomatic and supportive and there is no specific antidote. Limited data suggest that neither metoprolol nor hydrochlorothiazide is dialyzable. If justified, gastric lavage and/or activated charcoal can be administered.
Based on the expected pharmacologic actions and recommendations for other beta adrenergic blockers and hydrochlorothiazide, the following measures should be considered when clinically warranted.
Hemodialysis is unlikely to make a useful contribution to metoprolol elimination [see Clinical Pharmacology (12.3)].
11 DESCRIPTION
Metoprolol tartrate and hydrochlorothiazide tablets, USP have the antihypertensive effect of metoprolol tartrate, a beta adrenoreceptor blocker, and hydrochlorothiazide, a thiazide diruetic. It is available as tablets for oral administration. The 50/25 tablets contain 50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; the 100/25 tablets contain 100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; and the 100/50 tablets contain 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide. Metoprolol tartrate is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is
Metoprolol tartrate, USP is a white, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Its molecular weight is 684.81.
Hydrochlorothiazide is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is
Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.74.
Inactive Ingredients:Anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch (corn) and sodium lauryl sulfate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
The mechanism of antihypertensive effect of thiazide diuretics is unknown.
12.2 Pharmacodynamics
Metoprolol
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.
There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.
The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6 to 12 hours.
12.3 Pharmacokinetics
Absorption
In man, absorption of metoprolol HCT is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.
Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1 to 2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6 to 1.8 times higher than in plasma.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
Effect of Food
Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.
Distribution
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.
Elimination
Thiazides are eliminated rapidly by the kidney. After oral administration of 25 mg to 100 mg doses, 72% to 97% of the dose is excreted in the urine, indicating dose-independent absorption.
Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10 to 17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9 to 30.0 L/hr; volume of distribution is 3.6 to 7.8 L/kg.
Specific Populations
Geriatric Patients
In elderly subjects with clinically normal renal function, there are no significant differences in metoprolol pharmacokinetics compared to young subjects.
Racial or Ethnic Groups
Metoprolol is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.
13 NONCLINICAL TOXICOLOGY
Metoprolol Tartrate and Hydrochlorothiazide Tablets: Carcinogenicity and mutagenicity studies have not been conducted with metoprolol tartrate and hydrochlorothiazide tablets. Metoprolol tartrate and hydrochlorothiazide tablets produced no evidence of impaired fertility in male or female rats administered gavaged doses up to 200/50 mg/kg (about 10 and 20 times the maximum recommended human dose (MRHD) of metoprolol and hydrochlorothiazide, respectively, on a mg/m2 basis) prior to mating and throughout gestation and rearing of young.
Metoprolol Tartrate: Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2- year study in rats at three oral dosage levels of up to 800 mg/kg per day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day (about 18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient.
Hydrochlorothiazide: Two-year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (about 120 times the MRHD of 25 mg/day on a mg/m2 basis) or in male and female rats at doses up to approximately 100 mg/kg/day (about 40 times the MRHD on a mg/m2 basis). However, there was equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity testor the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo 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 in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, and in the Aspergillus nidulans nondisjunction 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/day (about 20 and 1.6 times the MRHD, on a mg/m2 basis), respectively, prior to mating and throughout gestation.
16 HOW SUPPLIED/STORAGE AND HANDLING
Metoprolol Tartrate and Hydrochlorothiazide Tablets, USP are available containing 50 mg or 100 mg of metoprolol tartrate, USP and 25 mg or 50 mg of hydrochlorothiazide, USP providing for the following available combinations: 50 mg/25 mg, 100 mg/25 mg or 100 mg/50 mg.
The 50 mg/25 mg tablets are peach, round, scored tablets debossed with M above the score and 424 below the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0424-01
bottles of 100 tablets
The 100 mg/25 mg tablets are peach, oval, scored tablets debossed with M to the left of the score and 434 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0434-01
bottles of 100 tablets
The 100 mg/50 mg tablets are peach, capsule-shaped, scored tablets debossed with M to the left of the score and 445 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0445-01
bottles of 100 tablets
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
17 PATIENT COUNSELING INFORMATION
Advise patients to take metoprolol tartrate and hydrochlorothiazide tablets as directed, with or immediately following meals. If a dose is missed, advise the patient to take only the next scheduled dose (without doubling it). Advise patients to not discontinue metoprolol tartrate and hydrochlorothiazide tablets without consulting their healthcare provider.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Manufactured by:
Mylan Laboratories Limited
Hyderabad — 500 096, India
75091660
Revised: 5/2022
MXA:MPHCTZ:R3
PRINCIPAL DISPLAY PANEL – 50 mg/25 mg
NDC 0378-0424-01
Metoprolol
Tartrate and
Hydrochlorothiazide
Tablets, USP
50 mg/25 mg
Rx only 100 Tablets
Each tablet contains:
Metoprolol tartrate, USP 50 mg
Hydrochlorothiazide, USP 25 mg
Usual Dosage: See accompanying
prescribing information.
Keep this and all medication out of
the reach of children.
Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]
Protect from moisture.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Made in India
Mylan.com
RMXA0424A1
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Code No.: MH/DRUGS/AD/089
PRINCIPAL DISPLAY PANEL – 100 mg/25 mg
NDC 0378-0434-01
Metoprolol
Tartrate and
Hydrochlorothiazide
Tablets, USP
100 mg/25 mg
Rx only 100 Tablets
Each tablet contains:
Metoprolol tartrate, USP 100 mg
Hydrochlorothiazide, USP 25 mg
Usual Dosage: See accompanying
prescribing information.
Keep this and all medication out of
the reach of children.
Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]
Protect from moisture.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Made in India
Mylan.com
RMXA0434A1
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Code No.: MH/DRUGS/AD/089
PRINCIPAL DISPLAY PANEL – 100 mg/50 mg
NDC 0378-0445-01
Metoprolol
Tartrate and
Hydrochlorothiazide
Tablets, USP
100 mg/50 mg
Rx only 100 Tablets
Each tablet contains:
Metoprolol tartrate, USP 100 mg
Hydrochlorothiazide, USP 50 mg
Usual Dosage: See accompanying
prescribing information.
Keep this and all medication out of
the reach of children.
Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]
Protect from moisture.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Made in India
Mylan.com
RMXA0445A1
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Code No.: MH/DRUGS/AD/089
INGREDIENTS AND APPEARANCE
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| METOPROLOL TARTRATE AND HYDROCHLOROTHIAZIDE
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| Labeler - Mylan Pharmaceuticals Inc. (059295980) |