Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide (Page 2 of 8)

5.5 Patients with Hepatic Impairment

Amlodipine.Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2 ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Electrolyte and Metabolic Imbalances

Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets also contains olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

5.7 Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

5.8 Systemic Lupus Erythematosus

Hydrochlorothiazide. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.9 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

5. 10 Sprue-like Enteropathy

Olmesartan medoxomil. Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets in cases where no other etiology is identified.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets

In the controlled trial of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets, patients were randomized to olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets 40/10/25 mg, olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients < 65 years of age and patients ≥ 65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 mg. The most common reason for discontinuation with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:

Table 1
Adverse Reaction OM 40/AML10/HCTZ 25 mg(N = 574)n (%) OM 40/AML10 mg(N = 596)n (%) OM 40/HCTZ 25mg(N = 580)n (%) AML10/HCTZ 25 mg(N = 552)n (%)
Edema peripheral 44 (7.7) 42 (7) 6 (1) 46 (8.3)
Headache 37 (6.4) 42 (7) 38 (6.6) 33 (6)
Fatigue 24 (4.2) 34 (5.7) 31 (5.3) 36 (6.5)
Nasopharyngitis 20 (3.5) 11 (1.8) 20 (3.4) 16 (2.9)
Muscle spasms 18 (3.1) 12 (2) 14 (2.4) 13 (2.4)
Nausea 17 (3) 12 (2) 22 (3.8) 12 (2.2)
Upper respiratory tract infection 16 (2.8) 26 (4.4) 18 (3.1) 14 (2.5)
Diarrhea 15 (2.6) 14 (2.3) 12 (2.1) 9 (1.6)
Urinary tract infection 14 (2.4) 8 (1.3) 6 (1) 7 (1.3)
Joint swelling 12 (2.1) 17 (2.9) 2 (0.3) 16 (2.9)

Syncope was reported by 1% of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets subjects compared to 0.5% or less for the other treatment groups.

Olmesartan medoxomil

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.

The following adverse reactions occurred in < 1% but > 0.1% of patients in controlled clinical trials under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert physicians to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis

Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo

Gastrointestinal : anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia

General : allergic reaction, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease

Musculoskeletal System : arthralgia, arthrosis, muscle cramps*, myalgia

Psychiatric : sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization

Respiratory : dyspnea*, epistaxis

Skin and Appendages : angioedema, erythema multiforme, pruritus*, rash*, rash erythematous, rash maculopapular

Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

Urinary System : micturition frequency, micturition disorder, nocturia

Autonomic Nervous System: dry mouth, sweating increased

Metabolic and Nutritional: hyperglycemia, thirst

Hemopoietic: leukopenia, purpura, thrombocytopenia

* = events that occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following adverse reactions occurred in < 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Hydrochlorothiazide

Other adverse reactions 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: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions

Metabolic: hyperglycemia, glycosuria, hyperuricemia

Musculoskeletal: muscle spasm

Nervous System/Psychiatric: restlessness

Renal: renal failure, renal dysfunction, interstitial nephritis

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

Special Senses: transient blurred vision, xanthopsia

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