Combizar® [film-coated tab]

Therapharma [ United Lab ]

Class : Angiotensin II Antagonists, Diuretics

Contents Per Tab 50/12.5 mg Losartan K 50 mg, hydrochlorothiazide 12.5 mg.

Per Tab 100/25 mg Losartan K 100 mg, hydrochlorothiazide 25 mg
Indications Treatment of hypertension; for patients in whom combination therapy is
appropriate.
Dosage Adults: Usual Initial and Maintenance Dose: 1 tab of losartan 50 mg +
HCTZ 12.5 mg FDC once daily.

If patients do not respond adequately, adjust to a maximum dose of 2

tabs of losartan 50 mg + HCTZ 12.5 mg FDC daily or 1 tab of losartan
100 mg + HCTZ 25 mg FDC daily.

In general, the antihypertensive effect is attained within 3 weeks after

initiation of therapy.
Administration May be taken with or without food
Contraindications Hypersensitivity to any component of Combizar and to sulfonamide-
derived drugs; anuria. Pregnancy.
Warnings Use in pregnancy: When used in pregnancy during the 2nd and 3rd
trimesters, drugs that act on the renin-angiotensin system (eg, losartan)
can cause injury and even death to the developing fetus. When
pregnancy is detected, discontinue losartan as soon as possible.
Special Precautions Do not initiate use of losartan-HCTZ FDC in patients who are
intravascularly volume depleted (eg, those treated with high-dose
diuretics).

Losartan-HCTZ FDC is not recommended for patients with severe renal

impairment (creatinine clearance ≤30 mL/min) or patients with hepatic
impairment.

Based on pharmacokinetic data demonstrating significantly increased

plasma concentrations of losartan in cirrhotic patients, a lower dose
should be considered for patients with a history of hepatic impairment.
Hence, losartan-HCTZ FDC is not recommended for patients who
require dose titration with losartan.

Losartan may increase blood urea and serum creatinine in patients with
 bilateral renal artery stenosis or stenosis of the artery to a solitary
kidney. These changes in renal function may be reversible upon
discontinuation of therapy.

Use in lactation: It is not known whether losartan is excreted in human

milk. HCTZ appears in human milk. Because of the potential for adverse
effects on the nursing infant, a decision should be made to discontinue
nursing or discontinue the drug, taking into account the importance of
the drug to the mother.
Adverse Drug In general, treatment with losartan potassium-hydrochlorothiazide was
Reactions well tolerated. For the most part, adverse experiences have been mild
and transient in nature and have not required discontinuation of therapy.
In controlled clinical trials, discontinuation of therapy due to clinical
adverse experiences was required in only 2.8% and 2.3% of patients
treated with the combination and placebo, respectively.

The following adverse experiences were reported with losartan-

hydrochlorothiazide:

Body as a Whole: Abdominal pain, edema/swelling, asthenia/fatigue,

headache.

Cardiovascular: Palpitation.

Gastrointestinal: Diarrhea, nausea.

Musculoskeletal: Back pain.

Nervous/Psychiatric: Dizziness.

Respiratory: Dry cough, sinusitis, bronchitis, pharyngitis, upper

respiratory infection.

Skin: Rash.

Drug Interactions Losartan Potassium: When given concurrently, the following drugs may
interact with losartan:

Cimetidine: Increase of about 18% in AUC of losartan may occur but

with no effect on the pharmacokinetics of its active metabolite.

Phenobarbital: Reduction of about 20% in the AUC of losartan and that

of its active metabolite.
 Rifampicin and Fluconazole: Reduction in levels of losartan’s active
metabolite.

Potassium-sparing Diuretics (eg, spironolactone, triamterene, amiloride),

Potassium Supplements, or Salt Substitutes Containing Potassium:
Increases in serum potassium.

Hydrochlorothiazide (HCTZ): When given concurrently, the following

drugs may interact with HCTZ: 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.

Cholestyramine and Colestipol Resins: Absorption of HCTZ is impaired

in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the HCTZ and reduce its
absorption from the GIT by up to 85% and 43%, respectively.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly

hypokalemia.

Pressor Amines (eg, adrenaline): Possible decreased response to pressor

amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing (eg, tubocurarine): Possible

increased responsiveness to the muscle relaxant.

Lithium: Diuretics reduce the renal clearance of lithium and add a high
risk of lithium toxicity.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs can reduce

the diuretic, natriuretic and antihypertensive effects of HCTZ.

Pregnancy Category
(US FDA)
Category C: Either studies in animals have revealed adverse effects on
the foetus (teratogenic or embryocidal or other) and there are no
controlled studies in women or studies in women and animals are not
available. Drugs should be given only if the potential benefit justifies the
potential risk to the foetus.
in 2nd & 3rd trimesters.
 Category D: There is positive evidence of human foetal risk, but the
benefits from use in pregnant women may be acceptable despite the risk
(e.g., if the drug is needed in a life-threatening situation or for a serious
disease for which safer drugs cannot be used or are ineffective).
Storage Store at temperatures not exceeding 30°C.
Description Each film-coated tablet contains losartan potassium 50 mg and
hydrochlorothiazide 12.5 mg.

Each film-coated tablet contains losartan potassium 100 mg and

hydrochlorothiazide 25 mg.
Mechanism of Angiotensin II receptor antagonist/diuretic/antihypertensive.
Action
Pharmacology: Rationale of the Combination: Losartan and
hydrochlorothiazide (HCTZ) are used together in a once daily oral fixed-
dose combination (FDC) to manage hypertension. Losartan is a specific
and selective angiotensin II receptor antagonist while HCTZ is a thiazide
diuretic. The effects of both drugs on blood pressure are additive.
Greater antihypertensive efficacy is generally achieved by adding a
small dose of a thiazide diuretic eg, HCTZ to the angiotensin II receptor
antagonist. Losartan lowers blood pressure by selectively blocking the
AT1 receptor in vascular and other tissues to antagonize the actions of
angiotensin II. HCTZ, on the other hand, lowers blood pressure by
increasing the renal excretion of sodium. Losartan tends to reverse
hypokalemia caused by HCTZ.

Losartan Potassium: Angiotensin II is a potent vasoconstrictor, the

primary vasoactive hormone of the renin-angiotensin system and an
important component in the pathophysiology of hypertension. It also
stimulates aldosterone secretion by the adrenal cortex. Losartan and its
principal active metabolite block the vasoconstrictor and aldosterone-
secreting effects of angiotensin II by selectively blocking the binding of
angiotensin II to the AT1 receptor found in many tissues. There is also an
AT2 receptor found in many tissues but is not known to be associated
with cardiovascular homeostasis. In vitro binding studies indicate that
losartan is a reversible, competitive inhibitor of the AT1 receptor. The
active metabolite is 10-40 times more potent by weight than losartan and
appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

Neither losartan nor its active metabolite inhibits ACE, nor do they bind
to or block other hormone receptors or ion channels known to be
important in cardiovascular regulation.

Hydrochlorothiazide (HCTZ): Hydrochlorothiazide is a thiazide diuretic.

Thiazides increase the excretion of water by inhibiting the reabsorption
of sodium and chloride ions at the distal renal tubule. The natriuretic
effects are accompanied by a secondary loss of potassium and
bicarbonate which can cause a mild hypokalemic, hypochloremic,
metabolic alkalosis. Thiazides also decrease the elimination of calcium
and uric acid. Thiazide diuretics usually do not affect normal blood
pressure. When chronically administered, thiazide diuretics decrease
peripheral vascular resistance. The exact mechanism responsible for
lowered peripheral resistance is not known, however, excretion of
urinary sodium by the kidneys is required to achieve blood pressure
reduction. Initially, diuretics lower blood pressure by decreasing cardiac
output, plasma volume and extracellular fluid volume. Cardiac output
eventually returns to normal, plasma and extracellular fluid values return
slightly less than normal, but peripheral vascular resistance is reduced,
resulting in lower blood pressure.

Pharmacokinetics: The combination of losartan and

hydrochlorothiazide (HCTZ) is administered orally. The blood pressure-
lowering effect of losartan is additive with that of HCTZ.

Losartan Potassium: Following oral administration, losartan is well

absorbed but undergoes presystemic metabolism, forming an active
metabolite (E-3174) and other inactive metabolites. The systemic
bioavailability of losartan tablets is approximately 33%. Mean peak
concentrations of losartan and its active metabolites are reached in 1 hr
and in 3-4 hrs, respectively. There is no clinically significant effect on
the plasma concentration profile of losartan when the drug is
administered with a meal.

Both losartan and its metabolite are ≥99% bound to plasma proteins,
primarily albumin. The volume of distribution of losartan is relatively
low at 34 L.

Plasma concentrations of the active metabolite are higher than those of

losartan at all doses, Cmax and AUC for E-3174 are approximately 2 and
5-8 times greater than the corresponding values for losartan itself.

Following oral administration, the plasma concentration of losartan and

its active metabolite, decline polyexponentially, with terminal half-lives
of about 2 hrs (1.5-2.5 hrs) and 6-9 hrs, respectively. As anticipated from
their short half-lives, neither losartan nor its active metabolite
accumulates significantly in plasma during once daily dosing with 100
mg.

The plasma clearance of losartan and its active metabolite is about 600
mL/min and 50 mL/min, respectively. Losartan is extensively
metabolized in the liver. Approximately 35% of an oral dose is excreted
 in the urine as unchanged compound and metabolites. Only 4% of the
dose is eliminated unchanged via the kidneys. The renal clearance of
losartan is 74 mL/min. Approximately 6% of the dose is excreted in
urine as the active metabolite with a renal clearance of 26 mL/min.
Losartan and its metabolites are also eliminated by biliary excretion,
with 58% of an oral dose recovered in the feces.

Hydrochlorothiazide (HCTZ): Hydrochlorothiazide is variably absorbed

from the gastrointestinal tract depending on the formulation and dose.
The systemic bioavailability is approximately 50-60%. After oral
administration of HCTZ, diuresis begins within 2 hrs, peaks in about 4
hrs and lasts about 6-12 hrs. The duration of action ranges from 6-12 hrs.
The drug crosses the placenta, but not the blood-brain barrier and is
distributed in breast milk. HCTZ is not metabolized but is eliminated
unchanged within 24 hrs. The elimination t½ of HCTZ was originally
reported to range from 5.6-14.8 hrs when plasma levels were followed
for at least 24 hrs. A more recent study reports a mean elimination t½ of
2.5 hrs in patients with normal renal function. The elimination t½ is
estimated to increase 12-20 hrs in patients with severe renal disease (eg,
creatinine clearance <10 mL/min).

Drug Study Oct 2010

Submitter by:
Charmy A. Palomo, R.N.