Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: MSD (Pty) Ltd, 117 16th Road, Halfway House, South Africa, 1685
Safety and efficacy in children have not been established.
Should a woman become pregnant while receiving FORTZAAR, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (See sections 4.3 and 4.6).
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure).
Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
Dual blockade of RAAS through the combined use of FORTZAAR and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1,73 m²) (see section 4.3). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
In patients who are intravascularly volume-depleted (e.g. those treated with high-dose diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of FORTZAAR, or a lower starting dose should be used (see section 4.2). Periodic determination of serum electrolytes must be performed at appropriate intervals.
Hydrochlorothiazide, a component of FORTZAAR, therapy may impair glucose tolerance. Dosage adjustment of antidiabetic medicines including insulin, may be required (see section 4.5).
Hydrochlorothiazide, a component of FORTZAAR, may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. FORTZAAR should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with hydrochlorothiazide, a component of FORTZAAR, therapy. Hydrochlorothiazide, a component of FORTZAAR, therapy may precipitate hyperuricaemia and/or gout.
Concomitant administration of lithium with FORTZAAR may lead to toxic blood concentrations of lithium (see section 4.5).
FORTZAAR is not recommended for patients with hepatic impairment or severe renal impairment (see section 4.3 and section 4.2). As a consequence of inhibiting the reninangiotensin system, changes in renal function including renal failure have been reported.
Concomitant use of fluoroquinolones and ACE inhibitors/Renin-Angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolones or ACE inhibitors/Renin-Angiotensin receptor blockers.
FORTZAAR may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan (see section 4.3).
Concomitant use of other medicines that may increase serum potassium may lead to hyperkalaemia (see section 4.5).
In patients receiving hydrochlorothiazide, a component of FORTZAAR, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of hydrochorothiazide, as contained in FORTZAAR.
An increased risk of non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC] with increasing cumulative dose of hydrochlorothiazide has been observed in epidemiological studies. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer and advised to take preventive measures to reduce sun and artificial UVA exposure. Patients should regularly check their skin for new lesions and promptly report suspicious skin lesions to their physicians for evaluation. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous non-melanoma skin cancer (see also section 4.8).
FORTZAAR contains lactose. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take FORTZAAR.
In clinical pharmacokinetic trials no interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital (see hydrochlorothiazide, alcohol, barbiturates or narcotics below) ketoconazole and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of the active metabolite of FORTZAAR. The clinical consequences of these interactions have not been evaluated.
Concomitant use of medicines that block angiotensin II or its effects and potassium-sparing diuretics (e.g. spironolactone, triamterene and amiloride), potassium supplements, salt substitutes containing potassium, or other medicines that may increase serum potassium (e.g. trimethoprim-containing products) may lead to increases in serum potassium.
Lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully, if lithium salts are co-administered with FORTZAAR.
Non-steroidal anti-inflammatory medicines (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of FORTZAAR.
In patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted including those on diuretic therapy) being treated with non-steroidal antiinflammatory drugs (NSAIDs), the co-administration of FORTZAAR may result in a further deterioration of renal function, including possible acute renal failure. Therefore, the combination should be administered with caution in patients with compromised renal function.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see section 4.3 and section 4.4).
Concomitant use of fluoroquinolones and ACE inhibitors/Renin-Angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3).
When administered concurrently, the following medicines may interact with HCTZ diuretics:
Alcohol, barbiturates, or narcotics: potentiation of orthostatic hypotension may occur.
Antidiabetic medication (oral agents and insulin): dosage adjustment of the antidiabetic medicine may be required.
Other antihypertensive medication: 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 percent, respectively. FORTZAAR should therefore be administered one hour before the intake of the resin.
Corticosteroids, ACTH or glycyrrhizin (found in liquorice): intensified electrolyte depletion, particularly hypokalaemia.
Pressor amines (e.g. norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants: response to non-depolarising agents may be increased.
Lithium: should not be given with FORTZAAR. Diuretic medicines reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with FORTZAAR (see section 4.3).
Non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 Inhibitors: the administration of these medicines can reduce the diuretic, natriuretic and antihypertensive effects of FORTZAAR.
Women of childbearing age should ensure effective contraception while on FORTZAAR.
FORTZAAR is contraindicated for use during pregnancy (see section 4.3). When pregnancy is planned or confirmed, FORTZAAR should be discontinued. Medicines affecting the reninangiotensin system, such as FORTZAAR, can cause foetal and neonatal morbidity and mortality when administered to pregnant women.
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. Women taking FORTZAAR should not breastfeed their infants (see section 4.3).
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No studies on the reactions on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.
In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with FORTZAAR and are shown in decreasing order of frequency within body system: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100) and rare (≥1/10 000, <1/1 000)
Common: dizziness
Common: asthenia/fatigue
In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with losartan potassium and are shown in decreasing order of frequency within body system: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100) and rare (≥1/10 000, <1/1 000)
Common: upper respiratory infection
Common: insomnia
Very common: headache
Common: dizziness
Common: palpitation, tachycardia
Uncommon: orthostatic hypotension
Common: cough, pharyngitis, nasal congestion, sinus disorder
Common: diarrhoea, nausea, abdominal pain, dyspepsia
Uncommon: rash
Common: back pain, muscle cramps
Common: asthenia/fatigue, oedema/swelling, chest pain
Common: hyperkalaemia, elevations of ALT
In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with hydrochlorothiazide and are shown in decreasing order of frequency within body system:
Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Common: (≥1/100, <1/10), uncommon; (≥1/1000, <1/100), rare: (≥1/10000, <1/1000), very rare: (>1/10000, including isolated reports).
Rare: thrombocytopenia
Very rare: leukopenia; agranulocytosis; haemolytic anaemia
Uncommon: anorexia; hyperuricaemia
Rare: hyperglycaemia
Rare: paraesthesia; headache
Uncommon: hypotension, (including orthostatic hypotension)
Very rare: respiratory distress including pneumonitis and pulmonary oedema
Uncommon: nausea; vomiting
Rare: diarrhoea; constipation
Very rare: pancreatitis
Rare: jaundice (intrahepatic cholestatic jaundice)
Uncommon: rash; urticaria
Rare: photosensitivity
Very rare: necrotising angiitis (vasculitis and cutaneous vasculitis)
Rare: glycosuria
The following clinical trials side effects have been reported with the use of either losartan or hydrochlorothiazide, but the frequencies are unknown:
Infections and infestations: Sialadenitis
Blood and the lymphatic system disorders: Aplastic anaemia
Metabolic and nutrition disorders: Electrolyte imbalance including hyponatraemia and hypokalaemia
Psychiatric disorders: Restlessness
Eye disorders: Xanthopsia, transient blurred vision
Ear and labyrinth disorders: Vertigo
Vascular disorders: Hypotension and/or postural hypotension
Gastrointestinal disorders: Gastric irritation
Skin and subcutaneous tissue disorders: Purpura
Musculoskeletal, connective tissue and bone disorders: Cramping, muscle spasm
Renal and urinary disorders: Renal dysfunction, interstitial nephritis, renal failure
General disorders and administration site conditions: Fever, weakness
The following adverse reactions have been reported in post-marketing experience; they are derived from spontaneous reports for which precise incidences cannot be determined therefore, the frequency is unknown:
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma).
Blood and the lymphatic system disorders: Thrombocytopenia, anaemia, aplastic anaemia, haemolytic anaemia, leukopenia, agranulocytosis
Immune system disorders: Anaphylactic reactions, including angioedema, swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported in patients treated with FORTZAAR; some of these patients previously experienced angioedema with other medicines including ACE inhibitors.
Metabolism and nutrition disorders: Anorexia, hyperglycaemia, hyperuricaemia, electrolyte imbalance including hyponatraemia and hypokalaemia
Psychiatric disorders: Insomnia, restlessness
Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias
Eye disorders: Xanthopsia, transient blurred vision
Cardiac disorders: Palpitation, tachycardia
Vascular disorders: Dose-related orthostatic effects, necrotising angiitis (vasculitis) (cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders: Cough, nasal congestion, pharyngitis, sinus disorder, upper respiratory infection, respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhoea, constipation, nausea, vomiting pancreatitis, sialadenitis
Hepato-biliary disorders: Hepatitis, jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders: Rash, pruritus, purpura (including Henoch-Schoenlein purpura), toxic epidermal necrolysis, urticaria, erythroderma, photosensitivity, cutaneous lupus erythematosus
Musculoskeletal, connective tissue, and bone disorders: Back pain, muscle cramps, muscle spasm, myalgia, arthralgia
Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure
Reproductive system and breast disorders: Erectile dysfunction/impotence
General disorders and administration site conditions: Chest pain, oedema/swelling, malaise, fever, weakness
Investigations: Liver function abnormalities
Based on available data from epidemiological studies, a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (BCC and SCC) has been observed.
The largest study included a population comprised of 71 533 cases of BCC and 8 629 cases of SCC matched to 1 430 833 and 172 462 population controls, respectively. High cumulative hydrochlorothiazide use (≥50000 mg) was associated with an adjusted odds ratio (OR) of 1,29 (95 % CI: 1,23-1,35) for BCC and 3,98 (95 % CI: 3,68-4,31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study evaluated the association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63 067 population controls. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2,1 (95 % CI: 1,7-2,6) for ever-use, increasing to an OR of 3,9 (95 % CI: 3,0-4,9) for high use (≥25000 mg) and an OR of 7,7 (95 % CI: 5,7-10,5) for the highest cumulative dose (≥100000 mg).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
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