Metoprolol tartrate/Hydrochlorothiazide

Uses and Indications

Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. This reduction in blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, particularly strokes and myocardial infarctions.

This fixed-combination drug is not intended for initial therapy of hypertension. However, if the fixed combination represents a dose that has been titrated to meet the individual patient’s needs, it may offer a more convenient option than administering the separate components.

Limitations of Use

• The fixed-combination formulation is not indicated for initial therapy of hypertension.

Dosage and Administration

The recommended dosage of Metoprolol Tartrate and Hydrochlorothiazide is determined by individual titration, with the usual dose range for Hydrochlorothiazide being 12.5 to 50 mg per day and for Metoprolol Tartrate, 100 to 450 mg per day. The initial dosage of Metoprolol Tartrate tablets is typically 100 mg daily, which may be administered in single or divided doses.

For optimal blood pressure control, the dosage may be gradually increased. While once-daily dosing is effective, it is noted that lower doses, particularly 100 mg, may not sustain a full effect over a 24-hour period; therefore, larger or more frequent doses may be necessary.

The following dosage schedule may be utilized based on the available tablet formulations:

• For tablets containing 50 mg Hydrochlorothiazide and 25 mg Metoprolol Tartrate, the recommended dosage is 2 tablets per day, administered in single or divided doses.

• For tablets containing 100 mg Metoprolol Tartrate and 25 mg Hydrochlorothiazide, the dosage is 1 to 2 tablets per day, also in single or divided doses.

• For tablets containing 100 mg Metoprolol Tartrate and 50 mg Hydrochlorothiazide, the recommended dosage is 1 tablet per day, in single or divided doses.

Dosing regimens that exceed 50 mg of Hydrochlorothiazide per day are not recommended. If necessary, an additional antihypertensive agent may be introduced gradually, starting with 50% of the usual recommended starting dose to prevent an excessive drop in blood pressure.

Contraindications

Hypersensitivity to metoprolol tartrate, hydrochlorothiazide, or other sulfonamide-derived drugs is a contraindication. The use of this medication is also contraindicated in patients with cardiogenic shock or decompensated heart failure. Additionally, it should not be administered to individuals with sinus bradycardia, sick sinus syndrome, or heart block greater than first degree unless a permanent pacemaker is in place. Anuria is another condition that contraindicates the use of this medication.

Warnings and Precautions

Patients should be aware that abrupt cessation of Metoprolol Tartrate and Hydrochlorothiazide may exacerbate myocardial ischemia and worsen congestive heart failure. It is crucial to avoid discontinuing therapy prior to major surgery, as this may impair heart response to adrenergic stimuli, increasing anesthesia and surgical risks.

Cardiac Considerations

• Cardiac Failure: Sympathetic stimulation is vital in congestive heart failure; beta blockade may further depress myocardial contractility and worsen heart failure. Administer metoprolol cautiously in hypertensive patients with controlled congestive heart failure. If cardiac failure develops, patients should be fully digitalized and/or given a diuretic, and metoprolol should be withdrawn if failure persists.

• Ischemic Heart Disease: Patients should be cautioned against therapy interruption without physician advice, as continued beta-blockade may lead to cardiac failure and abrupt cessation may exacerbate angina pectoris or cause myocardial infarction.

Respiratory Precautions

• Bronchospastic Diseases: Patients with bronchospastic diseases should generally avoid beta-blockers. If metoprolol is used, it should be done cautiously and in conjunction with a beta-2-stimulating agent.

Diabetes Management

• Diabetes and Hypoglycemia: Metoprolol may mask symptoms of hypoglycemia and alter glucose levels; therefore, diabetic patients should be monitored closely.

Endocrine Considerations

• Thyrotoxicosis: Abrupt withdrawal of metoprolol in patients with thyrotoxicosis may precipitate a thyroid storm, and beta blockade may mask signs of hyperthyroidism.

Pheochromocytoma

• In patients with pheochromocytoma, therapy with metoprolol should only be initiated after starting an alpha blocker to avoid paradoxical blood pressure increases.

Monitoring Requirements

• Electrolyte and Renal Function Monitoring: Serum electrolytes and creatinine should be monitored periodically, especially in patients with a history of renal impairment or those receiving thiazide therapy. Warning signs of electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, tachycardia, and gastrointestinal disturbances. Hypokalemia may develop, particularly with brisk diuresis or severe cirrhosis, and potassium supplements may be necessary.

• Laboratory Tests: Initial and periodic serum electrolyte determinations should be performed to detect possible imbalances, especially in patients vomiting excessively or receiving parenteral fluids. Clinical laboratory findings may include elevated serum transaminase, alkaline phosphatase, and lactate dehydrogenase levels.

Additional Considerations

• Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Caution is advised in patients with peripheral vascular disease, as metoprolol can aggravate symptoms of arterial insufficiency.

In summary, careful monitoring and management are essential for patients taking Metoprolol Tartrate and Hydrochlorothiazide, particularly those with underlying health conditions or undergoing significant medical procedures.

Side Effects

Patients receiving Metoprolol Tartrate and Hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Boxed Warnings

• Abrupt cessation of therapy may exacerbate myocardial ischemia.

• The medication may worsen congestive heart failure.

• Bronchospasm may occur; beta-blockers should be avoided in such cases.

• Bradycardia is a potential risk.

• Discontinuation of therapy prior to major surgery should be avoided.

• In patients with diabetes, the medication may mask symptoms of hypoglycemia and alter glucose levels; monitoring is advised.

• Serum electrolytes and creatinine should be monitored periodically.

• Peripheral vascular disease may be aggravated, worsening symptoms of arterial insufficiency.

• In patients with pheochromocytoma, therapy should first be initiated with an alpha blocker.

• Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm.

• Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Serious Adverse Reactions

• Cardiovascular Events:

  • Bradycardia and bradyarrhythmia

  • Hypotension

  • Heart failure

  • Cardiac conduction disturbances

  • Atrioventricular block

  • Cardiogenic shock

• Respiratory:

  • Bronchospasm

  • Hypoxia

• Neurological:

  • Impairment of consciousness or coma

Common Adverse Reactions (Frequency ≥ 1%)

• Body as a Whole:

  • Fatigue or lethargy: reported in approximately 10% of patients.

  • Flu syndrome: reported in approximately 10% of patients.

• Nervous System:

  • Dizziness or vertigo: occurred in about 10% of patients.

  • Drowsiness or somnolence: occurred in about 10% of patients.

  • Headache: occurred in about 10% of patients.

  • Nightmares: occurred in about 1% of patients.

• Cardiovascular:

  • Bradycardia: occurred in about 6% of patients.

  • Decreased exercise tolerance: occurred in about 1% of patients.

  • Dyspnea: occurred in about 1% of patients.

• Digestive:

  • Diarrhea: occurred in about 1% of patients.

  • Nausea or vomiting: occurred in about 1% of patients.

  • Dry mouth: occurred in about 1% of patients.

  • Constipation: occurred in about 1% of patients.

• Metabolic and Nutritional:

  • Hypokalemia: occurred in fewer than 10% of patients.

  • Edema: occurred in about 1% of patients.

  • Gout: occurred in about 1% of patients.

  • Anorexia: occurred in about 1% of patients.

Rare Adverse Reactions

• Hematologic:

  • Agranulocytosis

  • Aplastic anemia

  • Thrombocytopenia

  • Nonthrombocytopenic purpura

• Hypersensitive Reactions:

  • Stevens-Johnson syndrome

  • Necrotizing angiitis

  • Respiratory distress, including pneumonitis and pulmonary edema

  • Urticaria

  • Rash

  • Photosensitivity

• Miscellaneous:

  • Confusional state

  • Visual disturbances

  • Hallucinations

  • Acute reversible syndrome characterized by disorientation, emotional lability, and decreased performance on neuropsychometrics.

Overdosage

Signs and symptoms of overdose may include:

• Bradycardia and bradyarrhythmia

• Hypotension

• Heart failure

• Cardiac conduction disturbances

• Bronchospasm

• Atrioventricular block

• Hypoxia

• Impairment of consciousness or coma

• Cardiogenic shock

• Nausea and vomiting

With thiazide diuretics, acute intoxication is rare, but may present with:

• Acute loss of fluid, electrolytes, and magnesium

• Hypotension

• Dizziness

• Muscle cramps

• Renal impairment or failure

• Sedation or impairment of consciousness

Altered laboratory findings can also occur, including hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased BUN.

Fetal/Neonatal Adverse Reactions

Neonates born to mothers receiving metoprolol during pregnancy may be at risk for:

• Hypotension

• Hypoglycemia

• Bradycardia

• Respiratory depression

Neonates should be observed for these symptoms and managed accordingly.

Drug Interactions

Concomitant use of metoprolol tartrate and hydrochlorothiazide with certain drug classes may lead to significant interactions that require careful monitoring and potential dosage adjustments.

Pharmacokinetic Interactions

• CYP2D6 Inhibitors: The presence of potent CYP2D6 inhibitors, such as fluoxetine, paroxetine, bupropion, thioridazine, quinidine, propafenone, ritonavir, diphenhydramine, hydroxychloroquine, terbinafine, and cimetidine, can increase the plasma concentration of metoprolol, necessitating close observation for adverse effects.

Pharmacodynamic Interactions

• Catecholamine-Depleting Drugs: The use of catecholamine-depleting agents (e.g., MAO inhibitors, reserpine) alongside metoprolol may result in additive hypotensive effects and bradycardia. Patients should be monitored for symptoms such as vertigo, syncope, or postural hypotension.

• Digitalis Glycosides: Co-administration of digitalis glycosides with metoprolol can enhance the risk of bradycardia due to the combined effects on atrioventricular conduction and heart rate.

• Clonidine: When metoprolol is used concurrently with clonidine, it is crucial to taper metoprolol several days before discontinuing clonidine to prevent rebound hypertension.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The antihypertensive, diuretic, and natriuretic effects of hydrochlorothiazide may be diminished when used with NSAIDs.

Special Considerations

• Antidiabetic Drugs: Patients on antidiabetic medications may require dosage adjustments when using hydrochlorothiazide, as insulin requirements can vary.

• Lithium: The renal clearance of lithium may be reduced by hydrochlorothiazide, increasing the risk of lithium toxicity.

• Hypokalemia: Hydrochlorothiazide can induce hypokalemia, which may heighten the cardiac toxicity of digitalis, leading to increased ventricular irritability.

• Absorption Impairment: The absorption of hydrochlorothiazide can be significantly reduced by anionic exchange resins such as cholestyramine and colestipol, with reductions of up to 85% and 43%, respectively.

• Laboratory Test Interactions: Thiazides may lower serum levels of protein-bound iodine without causing thyroid dysfunction and should be discontinued prior to parathyroid function tests.

These interactions highlight the importance of monitoring and adjusting treatment regimens when prescribing metoprolol tartrate and hydrochlorothiazide in conjunction with other medications.

Pediatric Use

Safety and effectiveness of Metoprolol Tartrate and Hydrochlorothiazide in pediatric patients have not been established. There are no available data to support the use of this medication in children or adolescents. Therefore, caution is advised when considering treatment options for this population.

Geriatric Use

Clinical studies of metoprolol tartrate and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

Hydrochlorothiazide is substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Given that elderly patients are more likely to have decreased renal function, careful consideration should be given to dose selection. It may be beneficial to monitor renal function in this population.

In general, dose selection for elderly patients should be cautious, typically starting at the low end of the dosing range. This approach reflects the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Pregnancy

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 the use of metoprolol during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta blockers, including metoprolol. Rare reports of jaundice, thrombocytopenia, and electrolyte imbalances have been noted 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 the daily dose of 200 mg in a 60-kg patient. The combination of metoprolol tartrate and hydrochlorothiazide administered to rats from mid-late gestation through lactation also resulted in increased post-implantation loss and decreased neonatal survival. Hydrochlorothiazide, when administered to pregnant mice and rats during organogenesis at high doses, produced no harm to the fetus, but thiazides cross the placental barrier and may appear in cord blood.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that neonates be observed for these symptoms and managed accordingly.

The estimated background risk of major birth defects and miscarriage for the general population is unknown, but in clinically recognized pregnancies, the estimated background risk of major birth defects is 2 to 4%, and the risk of miscarriage is 15 to 20%. Untreated hypertension during pregnancy can lead to adverse outcomes for both the mother and the fetus, including increased risks for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Pregnant women with hypertension should be carefully monitored and managed.

Metoprolol tartrate and hydrochlorothiazide are classified as Pregnancy Category C, indicating that these medications should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of these medications in pregnant women, and the potential risks should be weighed against the benefits in managing maternal hypertension.

Lactation

There are limited data on the presence of metoprolol tartrate and hydrochlorothiazide in human milk, as well as their effects on breastfed infants and milk production. However, available literature indicates that both metoprolol and hydrochlorothiazide are excreted in breast milk. The estimated daily dose of metoprolol received by a breastfed infant is less than 1 mg, which corresponds to approximately 0.5% to 2% of the mother’s weight-adjusted dosage.

Monitoring of breastfed infants exposed to metoprolol tartrate and hydrochlorothiazide is recommended for signs of drowsiness, poor feeding, bradycardia, or somnolence. There have been no reported adverse effects on breastfed infants from exposure to these medications during lactation. However, doses of hydrochlorothiazide that lead to clinically significant diuresis may impair milk production, while the effects of metoprolol on milk production remain unclear.

In a small study, the average amount of metoprolol in breast milk was found to be 71.5 mcg/day, with a range of 17.0 to 158.7 mcg/day. A peak concentration of hydrochlorothiazide was observed at 275 mcg/L in breast milk three hours after a 50 mg dose, with no detectable levels in the infant’s plasma at 2 and 11 hours post-dose.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for these medications and any potential risks to the breastfed child. If the use of metoprolol tartrate and hydrochlorothiazide is deemed essential, consideration should be given to the possibility of discontinuing breastfeeding.

Renal Impairment

In patients with renal impairment, careful consideration is required when administering Metoprolol Tartrate and Hydrochlorothiazide. Thiazide diuretics should be used with caution, particularly in those with severe renal disease, as they may precipitate azotemia. Additionally, the cumulative effects of the medication can develop in individuals with impaired renal function, necessitating close monitoring.

It is essential to monitor serum electrolytes and creatinine levels periodically to assess renal function and prevent potential complications. Regular evaluation will help ensure that any necessary dosing adjustments can be made in response to changes in renal status.

Hepatic Impairment

Patients with hepatic impairment should use thiazides, such as Hydrochlorothiazide, with caution. Impaired hepatic function or progressive liver disease may lead to minor alterations in fluid and electrolyte balance, which could precipitate hepatic coma. There are no specific dosage adjustments, special monitoring requirements, or additional precautions provided for patients with liver problems regarding the use of Metoprolol Tartrate and Hydrochlorothiazide. Therefore, careful consideration and monitoring of these patients are advised when prescribing this medication.

Overdosage

In cases of overdosage with Metoprolol Tartrate and Hydrochlorothiazide, the most frequently observed signs associated with beta-adrenergic blocker overdose include bradycardia, bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, impairment of consciousness or coma, cardiogenic shock, nausea, and vomiting. For thiazide diuretics, acute intoxication is rare, but the primary feature of overdose is acute loss of fluid, electrolytes, and magnesium. Symptoms may manifest as hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness.

Altered laboratory findings may also be present, including hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN). It is important to note that several cases of metoprolol overdosage have been reported, some resulting in death, while no fatalities have been associated with hydrochlorothiazide.

Management of overdosage should occur in a medical facility equipped to provide appropriate supportive measures, monitoring, and supervision, as treatment is symptomatic and there is no specific antidote. Gastric lavage and/or activated charcoal may be administered if justified, although limited data suggest that neither metoprolol nor hydrochlorothiazide is dialyzable, and hemodialysis is unlikely to significantly contribute to metoprolol elimination.

For bradycardia and conduction disturbances, atropine, adrenergic-stimulating drugs, or a pacemaker may be utilized. In cases of hypotension or shock, it is essential to treat the underlying bradycardia, consider intravenous fluid expansion, and administer vasopressors or glucagon if necessary. Support for heart failure may involve treating bradycardia and using inotropes to support hemodynamics. Bronchospasm can typically be reversed with bronchodilators.

Continuous monitoring of fluid and electrolyte balance, particularly serum potassium, as well as renal function, is crucial until conditions stabilize.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects have been reported for metoprolol tartrate and hydrochlorothiazide. Studies indicate that these compounds produced no evidence of impaired fertility in male or female rats administered gavaged doses up to 200/50 mg/kg prior to mating and throughout gestation and rearing of young. Additionally, no evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times the daily dose of 200 mg in a 60 kg patient. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Carcinogenesis and Mutagenesis

Carcinogenicity and mutagenicity studies have not been conducted with metoprolol tartrate and hydrochlorothiazide. Long-term studies in animals have been performed to evaluate the carcinogenic potential of these compounds. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms. The only histologic changes observed 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, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose compared to untreated control animals. However, there was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This study was repeated in CD-1 mice, where 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, including 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, yielded negative results.

Impairment of Fertility

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

Animal Toxicology

Two-year feeding studies in mice and rats have uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. However, there was equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity test or the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, as well as in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Storage and Handling

Metoprolol Tartrate and Hydrochlorothiazide is supplied in tablet form.

Tablets should be stored at 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as per USP Controlled Room Temperature guidelines. An alternative storage range of 20° to 25°C (68° to 77°F) is also acceptable, with the same excursion limits.

It is essential to protect the tablets from moisture. They must be dispensed in a tight, light-resistant container as defined in the USP, utilizing a child-resistant closure.