Telmisartan and Hydrochlorothiazide 40 mg; 12.5 mg Tablet, 30-count

WARNINGS Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue telmisartan and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to telmisartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS , Pediatric Use ). No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 basis].

In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m 2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day).

Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Hypotension in Volume-Depleted Patients Initiation of antihypertensive therapy in patients whose renin-angiotensin system are activated such as patients who are intravascular volume- or sodium-depleted, e.g., in patients treated vigorously with diuretics, should only be approached cautiously. These conditions should be corrected prior to administration of telmisartan and hydrochlorothiazide tablets. Treatment should be started under close medical supervision (see DOSAGE AND ADMINISTRATION ).

If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindicati…

ADVERSE REACTIONS Telmisartan and hydrochlorothiazide tablets has been evaluated for safety in over 1700 patients, including 716 treated for over six months and 420 for over one year. In clinical trials with telmisartan and hydrochlorothiazide tablets, no unexpected adverse events have been observed. Adverse experiences have been limited to those that have been previously reported with telmisartan and/or hydrochlorothiazide.

The overall incidence of adverse experiences reported with the combination was comparable to placebo. Most adverse experiences were mild in intensity and transient in nature and did not require discontinuation of therapy. Adverse events occurring at an incidence of 2% or more in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.

TABLE 1 Adverse Events Occurring ≥2% of Telmisartan/Hydrochlorothiazide (HCTZ) Patients* Telm/HCTZ (N=414) (%) Placebo (N=74) (%) Telm (N=209) (%) HCTZ (N=121) (%) Body as a whole Fatigue 3 1 3 3 Influenza-like symptoms 2 1 2 3 Central/peripheral nervous system Dizziness 5 1 4 6 Gastrointestinal system Diarrhea 3 0 5 2 Nausea 2 0 1 2 Respiratory system disorder Sinusitis 4 3 3 6 Upper respiratory tract infection 8 7 7 10 * includes all doses of telmisartan (20 to 160 mg), hydrochlorothiazide (6.25 to 25 mg), and combinations thereof The following adverse events were reported at a rate less than 2% in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo: back pain, dyspepsia, vomiting, tachycardia, hypokalemia, bronchitis, pharyngitis, rash, hypotension postural, abdominal pain.

Finally, the following adverse events were reported at a rate of 2% or greater in patients treated with telmisartan/hydrochlorothiazide, but were as, or more common in the placebo group: pain, headache, cough, urinary tract infection. Adverse events occurred at approximately the same rates in men and women, older and younger patients, and black and non-black patients. In controlled trials (n=1017), 0.3% of patients treated with telmisartan and hydrochlorothiazide tablets 40/12.5 mg, 80/12.5 mg or 80/25 mg discontinued due to orthostatic hypotension, and the incidence of dizziness was 4%, 7%, and 1% respectively.

Telmisartan Other adverse experiences that have been reported with telmisartan, without regard to causality, are listed below: Autonomic Nervous System : impotence, increased sweating, flushing Body as a Whole : allergy, fever, leg pain, malaise, chest pain Cardiovascular : palpitation, dependent edema, angina pectoris, leg edema, abnormal ECG, hypertension, peripheral edema CNS : insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia Gastrointestinal : flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders Metabolic : gout, hypercholesterolemia, diabetes mellitus Musculoskeletal : arthritis, arthralgia, leg cramps, myalgia Psychiatric : anxiety, depression, nervousness Resistance Mechanism : infection, fungal infection, abscess, otitis media Respiratory : asthma, rhinitis, dyspnea, epistaxis Skin : dermatitis, eczema, pruritus Urinary : micturition frequency, cystitis Vascular : cerebrovascular disorder Special Senses : abnormal vision, conjunctivitis, tinnitus, earache A single case of angioedema was reported (among a total of 3781 patients treated with telmisartan).

Hydrochlorothiazide Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body as a whole : weakness Digestive : pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic : aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity…

Drug Interactions Telmisartan Aliskiren: Do not co-administer aliskiren with telmisartan and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with telmisartan and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min). Digoxin : When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed.

It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under-digitalization. Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Cases have also been reported with angiotensin II receptor antagonists including telmisartan.

Because lithium should not be used with diuretics, the use of lithium with telmisartan and hydrochlorothiazide is not recommended. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) : In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C max and AUC of ramipril 2.3 and 2.1 fold, respectively, and C max and AUC of ramiprilat 2.4 and 1.5 fold, respectively. In contrast, C max and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan.

Warfarin : Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR). Other Drugs : Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19.

Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19. Hydrochlorothiazide When administered concurrently, the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics : Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) : Dosage adjustment of the antidiabetic drug may be required.

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

Corticosteroids, ACTH : Intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) : Possible decreased respons…