Telmisartan/Hydrochlorothiazide

Uses and Indications

Telmisartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents, to effectively lower 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.

It is important to note that telmisartan and hydrochlorothiazide tablets are not indicated for initial therapy.

Limitations of Use

• Telmisartan and hydrochlorothiazide tablets should not be used as a first-line treatment for hypertension.

Dosage and Administration

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

For patients with biliary obstructive disorders or hepatic insufficiency, treatment should be initiated at a lower dose of 40 mg/12.5 mg once daily.

Telmisartan and Hydrochlorothiazide tablets can be taken with or without food. The clinical response should be evaluated after 2 to 4 weeks of therapy; if blood pressure remains uncontrolled, further titration to 160 mg/25 mg may be considered.

Patients with renal impairment may continue the usual regimen as long as their creatinine clearance is greater than 30 mL/min. However, Telmisartan and Hydrochlorothiazide are not recommended for patients with severe hepatic impairment, and treatment should commence under close medical supervision using the 40 mg/12.5 mg combination.

In cases where blood pressure is not adequately controlled with Telmisartan monotherapy at 80 mg, a switch to Telmisartan 80 mg/Hydrochlorothiazide 12.5 mg once daily may be appropriate, with titration to 160 mg/25 mg if necessary. Conversely, if blood pressure is inadequately controlled by 25 mg of Hydrochlorothiazide once daily, switching to either Telmisartan 80 mg/Hydrochlorothiazide 12.5 mg or Telmisartan 80 mg/Hydrochlorothiazide 25 mg once daily is recommended.

Contraindications

Telmisartan and hydrochlorothiazide are contraindicated in patients with hypersensitivity to telmisartan, hydrochlorothiazide, or any component of the product, including those with a history of anaphylaxis or angioedema. The use of this medication is also contraindicated in patients with anuria. Additionally, co-administration with aliskiren is contraindicated in patients with diabetes due to the potential for adverse effects.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, telmisartan and hydrochlorothiazide should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. The use of these drugs during the second and third trimesters of pregnancy may reduce fetal renal function and increase fetal and neonatal morbidity and mortality. Oligohydramnios resulting from this therapy can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. In cases where there is no appropriate alternative to therapy, the mother should be informed of the potential risks to the fetus, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, discontinuation of therapy should be considered unless it is deemed lifesaving for the mother.

Hypotension in Volume-Depleted Patients Initiation of antihypertensive therapy in patients whose renin-angiotensin system is activated, such as those who are intravascular volume- or sodium-depleted, should be approached cautiously. These conditions should be corrected prior to administration of telmisartan and hydrochlorothiazide.

General Precautions

• Avoid fetal or neonatal exposure.

• Correct volume or salt depletion before initiating therapy. Observe for signs and symptoms of hypotension.

• Monitor renal function and potassium levels in susceptible patients.

• Observe for clinical signs of fluid or electrolyte imbalance.

• Hypersensitivity reactions may occur, particularly in patients with a history of allergy or bronchial asthma.

• Hydrochlorothiazide can cause acute myopia and secondary angle-closure glaucoma, characterized by acute onset of decreased visual acuity or ocular pain. Discontinuation of hydrochlorothiazide is the primary treatment for this condition.

Laboratory Tests

• Monitor renal function and potassium levels in susceptible patients.

• Perform serial ultrasound examinations to assess the intra-amniotic environment in pregnant patients on therapy with drugs affecting the renin-angiotensin system.

Get Emergency Medical Help Patients experiencing hypotension should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. Anaphylactic reactions may also require immediate medical attention.

Stop Taking and Call Your Doctor Patients should discontinue telmisartan and hydrochlorothiazide if oligohydramnios is observed, unless it is considered lifesaving for the mother. Symptoms of acute angle-closure glaucoma, such as acute onset of decreased visual acuity or ocular pain, necessitate rapid discontinuation of hydrochlorothiazide.

Side Effects

Common adverse reactions occurring in patients treated with telmisartan and hydrochlorothiazide (≥2% incidence) include:

• Upper respiratory tract infection (8%)

• Dizziness (5%)

• Sinusitis (4%)

• Diarrhea (3%)

• Fatigue (3%)

• Influenza-like symptoms (2%)

• Nausea (2%)

Additional adverse reactions reported at a rate less than 2% but more common than in placebo groups include back pain, dyspepsia, vomiting, tachycardia, hypokalemia, bronchitis, pharyngitis, rash, hypotension (postural), and abdominal pain. In controlled trials, 0.3% of patients discontinued treatment due to orthostatic hypotension.

Serious adverse reactions may include:

• Fetal Toxicity: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. It is advised to discontinue telmisartan and hydrochlorothiazide as soon as pregnancy is detected. Use during the second and third trimesters can result in oligohydramnios, reduced fetal renal function, fetal lung hypoplasia, skeletal deformations, hypotension, and death.

• Hypersensitivity Reactions: These may include angioedema, urticaria, and other allergic reactions.

• Acute Myopia and Secondary Angle-Closure Glaucoma: These conditions have been reported in some patients.

Overdosage may lead to:

• Telmisartan: Hypotension, dizziness, tachycardia, and potential bradycardia due to parasympathetic stimulation.

• Hydrochlorothiazide: Electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

Post-marketing experience has identified additional adverse reactions, including headache, asthenia, edema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, increased blood pressure, hyperkalemia, syncope, dyspepsia, and renal impairment, among others. Rare cases of rhabdomyolysis have also been reported.

Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. It is important to correct any volume or salt depletion before initiating therapy and to observe for clinical signs of fluid or electrolyte imbalance.

Drug Interactions

Concomitant use of telmisartan and hydrochlorothiazide with certain medications may lead to significant interactions, which can be categorized into pharmacokinetic and pharmacodynamic interactions.

Pharmacokinetic Interactions

• Lithium: The combination of telmisartan and hydrochlorothiazide may increase the risk of lithium toxicity. It is advised to avoid the use of lithium with this combination due to the potential for elevated serum lithium concentrations.

• Digoxin: Co-administration of telmisartan with digoxin has been associated with median increases in digoxin peak plasma concentration (49%) and trough concentration (20%). Monitoring of digoxin levels is recommended when initiating, adjusting, or discontinuing telmisartan to prevent over- or under-digitalization.

• Cholestyramine and Colestipol: These anionic exchange resins can significantly reduce the absorption of hydrochlorothiazide, with cholestyramine reducing absorption by up to 85% and colestipol by 43%.

• Ramipril and Ramiprilat: Co-administration with telmisartan may increase the exposure to ramipril and ramiprilat, leading to enhanced pharmacodynamic effects.

Pharmacodynamic Interactions

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of telmisartan and hydrochlorothiazide. Additionally, there is an increased risk of renal impairment, particularly in elderly patients or those with compromised renal function. Regular monitoring of renal function is recommended.

• Dual Blockade of the Renin-Angiotensin System: The combination of telmisartan with other agents that block the renin-angiotensin system may increase the risk of renal impairment, hypotension, and hyperkalemia.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with telmisartan and hydrochlorothiazide.

• Other Antihypertensive Drugs: The combination may lead to an additive effect or potentiation of antihypertensive effects.

• Corticosteroids and ACTH: There may be intensified electrolyte depletion, particularly hypokalemia, when used with hydrochlorothiazide.

• Alcohol, Barbiturates, or Narcotics: These substances may potentiate orthostatic hypotension when used with hydrochlorothiazide.

• Skeletal Muscle Relaxants (e.g., Tubocurarine): There may be an increased responsiveness to nondepolarizing muscle relaxants when used with hydrochlorothiazide.

In summary, careful consideration and monitoring are advised when telmisartan and hydrochlorothiazide are used in conjunction with the aforementioned medications to mitigate potential adverse effects and ensure therapeutic efficacy.

Pediatric Use

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

Neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide may experience complications such as oliguria or hypotension. In such cases, it is crucial to support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical trials involving telmisartan and hydrochlorothiazide, approximately 20% of patients were 65 years of age or older, with 5% being 75 years of age or older. No overall differences in effectiveness and safety were observed between elderly patients and younger patients. However, clinical experience suggests that greater sensitivity may be present in some older individuals, which cannot be ruled out.

For elderly patients, dose selection should be approached with caution. It is generally recommended to start at the low 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. Regular monitoring of these patients is advised to ensure safety and efficacy.

Pregnancy

Telmisartan and hydrochlorothiazide 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 increased fetal and neonatal morbidity and mortality. When pregnancy is detected, telmisartan and hydrochlorothiazide should be discontinued as soon as possible.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death.

The use of RAS-affecting drugs in the second and third trimesters can result in oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Serial ultrasound examinations should be performed to assess the intra-amniotic environment in patients taking telmisartan and hydrochlorothiazide during pregnancy. If oligohydramnios is observed, the medication should be discontinued unless it is deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Infants with in utero exposure to telmisartan and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. If these conditions occur, supportive measures for blood pressure and renal perfusion may be necessary, including exchange transfusions or dialysis.

Thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. Hydrochlorothiazide should not be used to treat hypertension in pregnant women, as it does not prevent or alter the course of Edema, Proteinuria, Hypertension (EPH) gestosis (pre-eclampsia). The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

Lactation

There is limited information regarding the excretion of telmisartan and hydrochlorothiazide in human milk, as well as their effects on breastfed infants and milk production. However, studies indicate that hydrochlorothiazide is present in human milk, though the implications for breastfed infants remain unclear.

Telmisartan has been shown to be present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma within 4 to 8 hours post-administration. Due to the potential for serious adverse reactions in breastfed infants, including hypotension, hyperkalemia, and renal impairment, it is advised that lactating mothers refrain from breastfeeding while undergoing treatment with telmisartan and hydrochlorothiazide.

Infants with a history of in utero exposure to these medications should be closely monitored for signs of hypotension, oliguria, and hyperkalemia. If such symptoms occur, appropriate medical interventions, including support for blood pressure and renal function, may be necessary. The decision to continue breastfeeding or discontinue the medication should be made based on the importance of the drug to the mother and the potential risks to the infant.

Renal Impairment

Patients with renal impairment should be closely monitored for renal function and potassium levels, particularly those who are susceptible to changes in these parameters. While no specific dosage adjustments are indicated for patients with mild (creatinine clearance CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment, the safety and effectiveness of Telmisartan and Hydrochlorothiazide in patients with severe renal impairment (CrCl ≤30 mL/min) have not been established, and the use of this medication is not recommended in such cases.

Regular monitoring of renal function and potassium is essential to ensure patient safety and to mitigate potential risks associated with renal impairment.

Hepatic Impairment

Patients with hepatic impairment should use Telmisartan and Hydrochlorothiazide with caution. Specifically, thiazide diuretics may pose risks in individuals with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance could precipitate hepatic coma.

For patients with biliary obstructive disorders or hepatic insufficiency, it is recommended to initiate treatment under close medical supervision using the 40 mg/12.5 mg combination. Due to the majority of telmisartan being eliminated via biliary excretion, these patients may experience reduced clearance and elevated blood levels of the medication.

No specific dosage adjustments, special monitoring requirements, or additional precautions for patients with liver problems are provided in the available data.

Overdosage

In cases of overdosage with telmisartan, the most likely manifestations include hypotension, dizziness, and tachycardia. Bradycardia may also occur due to parasympathetic (vagal) stimulation. If symptomatic hypotension arises, it is recommended that supportive treatment be initiated. It is important to note that telmisartan is not removed by hemofiltration and is not dialyzable.

For hydrochlorothiazide overdose, the predominant signs and symptoms are typically related to electrolyte depletion, which may include hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. In instances where digitalis has been co-administered, hypokalemia may exacerbate the risk of cardiac arrhythmias. 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.

Due to the limited data available regarding telmisartan overdosage in humans, careful monitoring and supportive care are essential in managing any overdose situation.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were mentioned in the provided text.

Non-Teratogenic Effects

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day, which is approximately 13 times the maximum recommended human dose (MRHD) of telmisartan on a mg/m² basis. This dose resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Nonclinical Toxicology

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide. There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m² basis, about 59 and 13 times, respectively, the MRHD of telmisartan. These doses have been shown to provide average systemic exposures to telmisartan greater than 100 times and 25 times, respectively, the systemic exposure in humans receiving the MRHD of telmisartan (80 mg/day). Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level, including bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

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). However, the NTP found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo 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 in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, in the Mouse Lymphoma Cell (mutagenicity) assay, and in the Aspergillus nidulans non-disjunction assay.

Storage and Handling

Telmisartan and Hydrochlorothiazide tablets are supplied in various packaging configurations. They should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

To maintain product integrity, tablets should not be removed from their blisters or bottles until immediately before administration. Additionally, if stored in a bottle, it is important to keep the container tightly closed to protect the tablets from moisture and contamination.