Telmisartan/Hydrochlorothiazide

Description

Telmisartan and hydrochlorothiazide tablets, USP, are a combination of telmisartan, an orally active angiotensin II antagonist targeting the AT1 receptor subtype, and hydrochlorothiazide, a thiazide diuretic. Telmisartan is a non-peptide molecule with the chemical designation 4’-[(1,4’-dimethyl-2’-propyl2,6’-bi-1H-benzimidazol-1’-yl)methyl]-1,1’-biphenyl-2-carboxylic acid, exhibiting an empirical formula of C33H30N4O2 and a molecular weight of 514.63. It appears as a white to slightly yellowish solid, is practically insoluble in water across a pH range of 3 to 9, sparingly soluble in strong acids (except hydrochloric acid), and soluble in strong bases.

Hydrochlorothiazide is characterized as a white or practically white, odorless crystalline powder with a molecular weight of 297.74. It is slightly soluble in water and freely soluble in sodium hydroxide solution. Its chemical structure is defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2.

These tablets are formulated for oral administration in three dosage combinations: 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg of telmisartan and hydrochlorothiazide, respectively. Inactive ingredients include mannitol, sodium hydroxide, meglumine, povidone, sodium stearyl fumarate, lactose monohydrate, and magnesium stearate. The 40 mg/12.5 mg and 80 mg/12.5 mg tablets contain ferric oxide red as a coloring agent, while the 80 mg/25 mg tablets contain ferric oxide yellow. The 80 mg/25 mg formulation is hygroscopic and necessitates protection from moisture.

Uses and Indications

Telmisartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents, to effectively lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Limitations of Use: Telmisartan and hydrochlorothiazide tablets are not indicated for initial therapy in the management of hypertension.

Dosage and Administration

The usual starting dose for the medication is 80 mg/12.5 mg administered once daily. Based on the patient's response and tolerability, the dose may be titrated up to a maximum of 160 mg/25 mg as needed.

For patients with biliary obstructive disorders or hepatic insufficiency, it is recommended to initiate treatment at a lower dose of 40 mg/12.5 mg once daily. Careful monitoring of the patient's condition is advised during the titration process to ensure optimal therapeutic outcomes while minimizing potential adverse effects.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to telmisartan or any of its components. Additionally, it is contraindicated in individuals with anuria, as the absence of urine production may indicate severe renal impairment. Co-administration with aliskiren is contraindicated in patients with diabetes due to the increased risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of telmisartan and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to injury or death of the developing fetus. Healthcare professionals should be vigilant in avoiding fetal or neonatal exposure to these agents.

Prior to initiating therapy, it is essential to correct any volume or salt depletion. Clinicians should closely monitor patients for signs and symptoms of hypotension, as this can occur in susceptible individuals. Regular assessment of renal function and potassium levels is recommended, particularly in patients who may be at increased risk. Additionally, healthcare providers should remain alert for clinical signs of fluid or electrolyte imbalance, which may necessitate intervention.

Hypersensitivity reactions have been reported and should be taken into consideration when prescribing these medications. Furthermore, patients may experience acute myopia and secondary angle-closure glaucoma, which require immediate attention.

To ensure safe use, monitoring of renal function and potassium levels is advised for susceptible patients. This proactive approach will help mitigate potential risks associated with the therapy.

Side Effects

Patients receiving treatment with telmisartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions reported include upper respiratory tract infection, dizziness, sinusitis, diarrhea, fatigue, influenza-like symptoms, and nausea.

Serious warnings associated with this treatment include the potential for fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as telmisartan, can cause injury and death to the developing fetus. Therefore, it is imperative to discontinue the use of telmisartan and hydrochlorothiazide as soon as pregnancy is detected. Additionally, fetal or neonatal exposure should be avoided.

Healthcare providers should ensure that any volume or salt depletion is corrected prior to initiating therapy. Patients should be monitored for signs and symptoms of hypotension, and renal function and potassium levels should be assessed in susceptible individuals. Clinical signs of fluid or electrolyte imbalance should also be observed.

Other adverse reactions that may occur include hypersensitivity reactions, acute myopia, secondary angle-closure glaucoma, and anuria. There is a noted risk of hypersensitivity to telmisartan or any of its components. Caution is advised when co-administering with aliskiren in patients with diabetes.

In cases of overdosage, the most likely manifestations associated with telmisartan include hypotension, dizziness, and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. For hydrochlorothiazide, the most common signs and symptoms observed in overdose situations are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, along with dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

The use of certain medications in conjunction with this drug may lead to significant interactions that require careful consideration and management.

Lithium: Co-administration with this drug may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended to avoid potential adverse effects.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of this drug. Additionally, there is an increased risk of renal impairment. Patients should be monitored for renal function and blood pressure.

Dual Blockade of the Renin-Angiotensin System: When used in combination with agents that also block the renin-angiotensin system, there is an elevated risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and serum potassium levels is advised.

Antidiabetic Drugs: The use of this drug may necessitate dosage adjustments of antidiabetic medications. Blood glucose levels should be closely monitored to ensure effective glycemic control.

Cholestyramine and Colestipol: These agents may reduce the absorption of thiazide diuretics. It is recommended to separate the administration of thiazides from cholestyramine or colestipol to minimize this interaction.

Packaging & NDC

The table below lists all NDC Code configurations of Telmisartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in pediatric patients have not been established.

In neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide tablets, if oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion. In such cases, exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical trials involving 1,017 patients, approximately 20% of those treated with telmisartan/hydrochlorothiazide were aged 65 years or older, with 5% being 75 years or older. The data indicate that there were no overall differences in the effectiveness and safety of telmisartan/hydrochlorothiazide in these elderly patients compared to their younger counterparts.

However, while clinical experience has not consistently identified differences in responses between elderly and younger patients, it is important to note that greater sensitivity to the medication in some older individuals cannot be ruled out. Therefore, dose selection for geriatric patients should be approached with caution. It is generally recommended to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Healthcare providers should closely monitor elderly patients for any adverse effects and adjust dosages as necessary to ensure safety and efficacy in this population.

Pregnancy

Telmisartan and hydrochlorothiazide tablets can cause fetal harm when administered to pregnant patients. The use of drugs that act on the renin-angiotensin system (RAS) during the second and third trimesters of pregnancy is associated with reduced fetal renal function, leading to oligohydramnios, increased fetal and neonatal morbidity, and potential death. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not specifically distinguished RAS-affecting drugs from other antihypertensive agents.

Animal studies have demonstrated fetotoxicity with telmisartan only at maternally toxic doses. When pregnancy is detected, it is recommended to discontinue telmisartan and hydrochlorothiazide tablets as soon as possible. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively, and all pregnancies carry a background risk of adverse outcomes.

Hypertension during pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery. Additionally, hypertension can elevate fetal risks for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed.

In cases where there is no appropriate alternative to RAS-affecting therapy, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations are advised for patients taking telmisartan and hydrochlorothiazide tablets during pregnancy to assess the intra-amniotic environment, with fetal testing considered based on gestational age. If oligohydramnios is detected, discontinuation of the medication is warranted unless it is deemed lifesaving for the mother, keeping in mind that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Infants with in utero exposure to telmisartan and hydrochlorothiazide tablets should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, including potential exchange transfusions or dialysis. It is important to note that thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. Thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia) and should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

Lactation

There is no information regarding the presence of telmisartan and hydrochlorothiazide tablets or telmisartan in human milk, nor are there data on the effects on the breastfed infant or on milk production. Limited published studies indicate that hydrochlorothiazide is present in human milk; however, there is insufficient information to determine its effects on the breastfed infant or on milk production.

In animal studies, telmisartan has been shown to be present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration. Due to the potential for serious adverse reactions in breastfed infants, including hypotension, hyperkalemia, and renal impairment, it is advised that nursing women refrain from breastfeeding during treatment with telmisartan and hydrochlorothiazide tablets.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those who are susceptible to changes in these parameters. Regular assessment is essential to ensure safe and effective use of the medication in this population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Limited data are available regarding the overdosage of telmisartan in humans. The most likely manifestations of telmisartan overdosage include hypotension, dizziness, and tachycardia. Additionally, bradycardia may occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is recommended that supportive treatment be instituted to manage the condition effectively.

It is important to note that telmisartan is not removed by hemofiltration and is not dialyzable, which may influence the management approach in cases of overdose.

In contrast, the most common signs and symptoms observed in patients with hydrochlorothiazide overdose are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias, necessitating careful monitoring and management of the patient's electrolyte levels.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established, and the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. This information may be relevant for healthcare professionals when considering the potential risks and management strategies for patients experiencing an overdose of hydrochlorothiazide.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. The combination of telmisartan and hydrochlorothiazide has not been evaluated for carcinogenicity, mutagenicity, or fertility. However, individual studies on telmisartan indicated no evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. Genotoxicity assays for telmisartan did not demonstrate any effects at the gene or chromosome level.

In terms of reproductive performance, no drug-related effects were noted in male and female rats at a dose of 100 mg/kg/day. Similarly, two-year feeding studies with hydrochlorothiazide revealed no evidence of carcinogenic potential in female mice or in male and female rats. Hydrochlorothiazide was also found to be non-genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations.

Furthermore, hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively.

Postmarketing Experience

No postmarketing experience details are available in the provided text.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly. This document contains essential information regarding the medication, including its indications, usage instructions, potential side effects, and important safety information. Emphasizing the importance of understanding this material can help patients make informed decisions about their treatment and enhance adherence to prescribed therapies.

Storage and Handling

The product is supplied in blister packs and bottles, with specific handling and storage requirements to ensure its integrity and efficacy.

It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F). To maintain optimal conditions, it is essential that tablets remain in their original blisters or bottles until just prior to administration. This practice helps to protect the tablets from environmental factors that could compromise their quality.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the activity of the renin-angiotensin system. Additionally, it is important to periodically assess serum electrolytes in these patients to ensure safety and efficacy.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Telmisartan and Hydrochlorothiazide as submitted by Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)