Orbas Plus

Approved Indications:

• Hypertension (Primary/Essential):
  Indicated for the treatment of hypertension in patients whose blood pressure is not adequately controlled with monotherapy of olmesartan medoxomil or hydrochlorothiazide.
• Initial Therapy for Hypertension:
  May be used as initial treatment in patients likely to need multiple drugs to achieve blood pressure goals, particularly those with Stage 2 hypertension or significantly elevated baseline blood pressure.

Off-Label or Clinically Accepted Uses:

• Hypertension with Proteinuria in Type 2 Diabetes:
  Utilized off-label to manage proteinuria in hypertensive diabetic patients to delay renal disease progression.
• Resistant Hypertension:
  Used in combination regimens when multiple agents are required to achieve blood pressure control.

Route: Oral

Adults:

• Starting Dose:
  Olmesartan 20 mg + Hydrochlorothiazide 12.5 mg once daily.
• Titration:
  If further blood pressure reduction is required, increase to:
• 40 mg / 12.5 mg
• 40 mg / 25 mg once daily (max dose).
• Time to Full Effect: Blood pressure lowering is typically seen within 1–2 weeks; full effect may take up to 4 weeks.

Available Fixed Combinations:

• 20 mg / 12.5 mg
• 40 mg / 12.5 mg
• 40 mg / 25 mg

Pediatrics:

• Not recommended. Safety and efficacy have not been established in children.

Elderly:

• No specific dose adjustment required; however, start at lower end of dosing range and monitor renal function and blood pressure carefully.

Renal Impairment:

• Mild to Moderate (CrCl 30–60 mL/min): Use with caution.
• Severe (CrCl <30 mL/min): Contraindicated due to risk of profound hypotension and volume depletion.

Hepatic Impairment:

• Use with caution. Not recommended in severe hepatic dysfunction due to altered drug metabolism and risk of hypotension.

Administration Notes:

• Administer once daily, preferably in the morning.
• Can be taken with or without food.
• Do not chew, crush, or split the tablet.

This combination consists of two agents working synergistically:

• Olmesartan Medoxomil: A prodrug that is converted in the gastrointestinal tract to olmesartan, a selective angiotensin II type 1 (AT1) receptor antagonist (ARB). It inhibits vasoconstriction and aldosterone secretion mediated by angiotensin II, resulting in vasodilation, reduced vascular resistance, and decreased blood pressure.
• Hydrochlorothiazide: A thiazide diuretic that acts on the distal convoluted tubule in the kidney to inhibit sodium-chloride symport, increasing the excretion of sodium, chloride, and water. This reduces plasma volume and cardiac output, contributing to blood pressure reduction.

Together, these drugs target both vascular tone and volume overload, producing additive antihypertensive effects.

Olmesartan:

• Absorption: Rapid and complete hydrolysis of the prodrug.
• Bioavailability: ~26%
• Peak Plasma Level: 1–2 hours post-administration
• Protein Binding: ~99%
• Metabolism: Minimal hepatic metabolism
• Half-life: ~13 hours
• Excretion: 35–50% in urine, remainder in feces

Hydrochlorothiazide:

• Absorption: Rapid
• Bioavailability: ~60–70%
• Peak Plasma Time: 1–2.5 hours
• Protein Binding: ~40–70%
• Metabolism: Not metabolized
• Half-life: 6–15 hours
• Excretion: ~95% unchanged in urine

• Pregnancy:
• Category D (Second and Third Trimesters):
  Associated with fetal hypotension, renal failure, skull hypoplasia, and even fetal death. Discontinue immediately when pregnancy is detected.
• Lactation:
• Hydrochlorothiazide: Excreted in breast milk; may decrease milk production.
• Olmesartan: Unknown excretion; avoid use during breastfeeding.
• Alternative therapy is recommended if breastfeeding is essential.

• Primary Class: Antihypertensive
• Subclass:
• Olmesartan: Angiotensin II Receptor Blocker (ARB)
• Hydrochlorothiazide: Thiazide Diuretic
• Combination Type: Fixed-dose combination (dual therapy)

• Hypersensitivity to olmesartan, hydrochlorothiazide, or any sulfonamide-derived drugs
• Pregnancy
• Severe renal impairment (CrCl <30 mL/min) or anuria
• Concomitant use with aliskiren in diabetic patients
• Refractory hypokalemia, hyponatremia, or hypercalcemia
• Hepatic coma or severe hepatic impairment

• Fetal Toxicity: Discontinue as soon as pregnancy is identified.
• Volume or Salt Depletion: May cause symptomatic hypotension; correct before initiating therapy.
• Electrolyte Imbalance: Monitor potassium, sodium, and magnesium levels regularly.
• Hyperuricemia: May exacerbate gout in susceptible patients.
• Photosensitivity: Increased risk of sunburn with hydrochlorothiazide.
• Sprue-like Enteropathy (Olmesartan): Reported with chronic diarrhea and weight loss.
• Renal Dysfunction: Monitor serum creatinine and eGFR; dose adjustments may be necessary.
• Impaired Hepatic Function: Risk of systemic hypotension; use with caution.
• Systemic Lupus Erythematosus (SLE): Thiazides may exacerbate or activate SLE.

Common (≥1%):

• General: Fatigue, dizziness, headache
• Gastrointestinal: Nausea, abdominal pain
• Metabolic: Hypokalemia, hyperuricemia, hyperglycemia
• Renal: Elevated serum creatinine, BUN
• Dermatologic: Photosensitivity

Serious and Rare:

• Angioedema
• Severe hypotension
• Acute kidney injury
• Sprue-like enteropathy
• Stevens-Johnson Syndrome (extremely rare)

Timing:
Adverse effects typically occur within the first 2–4 weeks; some like dermatologic or GI issues may appear later.

• NSAIDs: May reduce the antihypertensive effect and increase the risk of renal impairment.
• Potassium Supplements & Potassium-Sparing Diuretics: Increased risk of hyperkalemia.
• Lithium: Increased serum lithium levels and risk of toxicity.
• Insulin & Oral Antidiabetics: Thiazides may decrease glucose tolerance.
• Alcohol, Barbiturates, Narcotics: May enhance hypotensive effect.
• Cholestyramine/Colestipol: May impair hydrochlorothiazide absorption.
• CYP450: Olmesartan has minimal CYP involvement, reducing risk of hepatic interactions.

• FDA: Labeling now includes sprue-like enteropathy warning (olmesartan-related).
• AHA/ACC (2023): Supports fixed-dose combinations for faster BP control in Stage 2 hypertension.
• NICE: ARB + thiazide combinations preferred over ACEi + thiazide in patients intolerant to ACE inhibitors.
• KDIGO (Chronic Kidney Disease): ARB-based regimens preferred for patients with proteinuria and hypertension.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Allowable range: 15°C to 30°C (59°F to 86°F)
• Humidity/Light: Protect from moisture and direct light
• Handling:
• Store in original packaging
• Do not crush or split tablets
• Keep out of reach of children