Terazosin 5mg Tablets
1. NAME OF THE MEDICINAL PRODUCT
Terazosin 5 mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5.935 mg of terazosin hydrochloride dihydrate equivalent to 5mg of terazosin.
For excipients see 6.1.
3. PHARMACEUTICAL FORM
Tablet
Mottled tan, round, flat tablet with bevelled edges, embossed with “93” on one-side and “762” on the other side
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Terazosin Tablets are indicated for:
The treatment of mild to moderate hypertension.
The symptomatic treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).
4.2. Posology and Method of Administration.
For oral use.
For the different dosage regimens suitable strengths are available. The dose of terazosin should be adjusted according to the patient's response. The following is a guide to administration:
Initial dose:
The lowest single dose of 1 mg before bedtime for all patients which should not be exceeded. Strict compliance with this recommendation should be observed to minimise potential acute first-dose hypotensive episodes.
Subsequent doses:
Treatment of mild to moderate hypertension.
The single daily dosage may be increased by approximately doubling the dosage at weekly intervals to achieve the desired blood pressure response.
The maintenance dose needs to be adjusted to the patient’s response. 2 mg/day may be sufficient with increases up to 10 mg if necessary (clinical studies support the use of 2-10 mg as maintenance dose).
The maximum dose is 20 mg of terazosin per day and should not be exceeded.
Use with thiazide diuretics and other antihypertensive agents in the treatment of hypertension
When adding a thiazide diuretic or another antihypertensive agent to a patient's regimen the dose of terazosin should be reduced or discontinued and retitration carried out if necessary. Caution should be observed when terazosin is administered with thiazides or other antihypertensive agents as hypotension may develop.
Treatment of benign prostatic hyperplasia
The dose may be increased by approximately doubling at weekly or bi-weekly intervals to achieve the desired reduction in symptoms. The maintenance dose is usually 5 to 10 mg once daily. Improvements in symptoms have been detected as early as two weeks after starting treatment with terazosin.
At present there are insufficient data to suggest additional symptomatic relief with doses above 10 mg once daily.
Treatment should be initiated using the 1mg tablets during seven days, 2 mg tablets during 14 days and 5 mg tablets during 7 days. Response to treatment must be reviewed at four weeks. Transient side effects may occur at each titration step. If any side effects persist, consideration should be given to reducing the dose.
Renal insufficiency:
Pharmacokinetic studies indicate that patients with impaired renal function need no alteration in recommended dosage.
Children
Safety and efficacy in children has not been established.
Elderly
Pharmacokinetic studies in the elderly indicate that no major alteration in dosage recommendation is required. However, particular caution should be taken with the titration of the terazosin dose.
If administration is discontinued for more than several days, therapy should be re-instituted using the initial dosage regimen.
Use in patients with hepatic insufficiency:
The terazosin dose should be titrated with particular caution in patients with impaired liver function since terazosin undergoes extensive hepatic metabolism and is mainly excreted by the biliary tract. No clinical experience is available in patients with severe hepatic dysfunction.
Method of administration:
The first tablet of a defined dose strength should be taken in the evening at bedtime. The following tablets of the same strength may be taken in the morning. The tablets should be taken with sufficient amount of liquid (i.e. 1 glass of water).
Terazosin therapy of hypertension is a long-term treatment, which should only be interrupted on medical advice. If it is necessary to stop terazosin therapy, the dose should be re-titrated starting with 1 mg terazosin at bedtime.
4.3. Contra-Indications
Terazosin is contra-indicated:
- In patients with a known hypersensitivity to the active ingredient, terazosin, other quinazolines (e.g. prazosin, doxazosin) or to any of the excipients.
- History of micturition syncope.
4.4 Special warnings and precautions for use
In clinical trials, the incidence of postural hypotension was greater in patients who received Terazosin for BPH than in patients who received Terazosin for hypertension. In this BPH indication, the incidence of postural hypotensive events was greater in patients aged 65 years and over (5.6%) than those aged less than 65 years (2.6%).
Patients should be warned for symptoms of postural hypotension and be advised to sit or lay down in case they occur (see also 4.7 Effects on ability to drive and use machines and 4.8 Undesirable effects).
Before treating the symptoms of BPH with alpha blockers, other causes of impaired urinary flow or urinary symptoms should be excluded. Also where the diagnosis of BPH has been established, it should be confirmed that there is no concomitant obstruction of the upper urinary tract or any signs of infection before treating with Terazosin.
Terazosin therapy requires regular medical monitoring. In the initial phase of therapy (especially after the first dose or when the Terazosin dose is increased) patients may experience a pronounced drop in blood pressure.
Dizziness, light-headedness, weakness, drowsiness and, in rare cases, syncope may occur.
This has also to be assumed in association with missed doses and subsequent re-initiation of Terazosin therapy. Patients should be cautioned about these possible adverse events and the circumstances in which they occur.
To minimise the risk of postural hypotension, patients should be monitored at the start of therapy. As the likelihood of such responses is greater with a higher than recommended starting dose, the recommended dosage regimen should be followed carefully. The patient should take the first dose of Terazosin at bedtime and should avoid abrupt changes in position or activities, which could be harmed by dizziness or weariness. This especially applies to the elderly.
Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and Terazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk for developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phospodiesterase-5-inhibitors.
Because of its vasodilator action, Terazosin should be used in caution in patients with any of the following cardiac conditions:
- Pulmonary oedema due to aortic or mitral stenosis
- High output cardiac insufficiency
- Right ventricular heart failure caused by pulmonary embolism or pericardial effusion
- Left ventricular heart failure with low filling pressure.
Caution is also recommended, when Terazosin is administered concomitantly with drugs, which may influence hepatic metabolism.
The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also been received with other alpha-1 blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.
Use in patients with hepatic insufficiency:
As for all medicaments metabolised in the liver, Terazosin should be used with particular caution in patients with impaired hepatic function. As there is no data available in patients with severe hepatic dysfunction, use of Terazosin in these patients is not recommended (see section 4.2).
This medicinal product should not be administered to patients with rare hereditary problems of galactose intolerance; the Lapp lactase deficiency or glucose-galactose malabsorption.
If administration is discontinued for more than several days, therapy should be re-instituted using the initial dosing regimen.
4.5 Interactions with other medicinal products and other forms of Interaction
In patients receiving terazosin plus ACE inhibitors or diuretics, the proportion reporting dizziness or related side effects was greater than in the total population of terazosin treated patients from clinical trials.
Caution should be observed when terazosin is administered with other antihypertensive agents, to avoid the possibility of significant hypotension. When adding terazosin to a diuretic or other antihypertensive agent, dosage reduction and retitration may be necessary.
Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and terazosin may lead to symptomatic hypotension in some patients (see section 4.4).
4.6. Pregnancy and Lactation
Although no teratogenic effects were seen in animal testing, the safety during pregnancy and lactation has not yet been established. Furthermore, data from animal studies show that terazosin may increase the duration of pregnancy or inhibit labour. Terazosin should not be used therefore in pregnancy unless the potential benefit outweighs the risk. Breast-feeding should be avoided.
4.7. Effects on Ability to Drive and Use Machines.
Dizziness, light-headedness or drowsiness may occur with the initial dose or in association with missed doses and subsequent reinitiation of terazosin therapy. Patients should be cautioned about these possible adverse events and the circumstances in which they may occur and advised to avoid driving or hazardous tasks for approximately the first 12 hours after the initial dose or when the dose is increased.
4.8 Undesirable effects
Terazosin, in common with other alpha-adrenoreceptor antagonists, may cause syncope. Syncopal episodes have occurred within 30 to 90 minutes of the initial dose of the drug. Syncope has occasionally occurred in association with rapid dosage increases or the introduction of another antihypertensive agent.
In clinical studies in hypertension, the incidence of syncopal episodes was approximately 1%. In most cases, this was believed to be due to an excessive postural hypotensive effect although occasionally the syncopal episode has been preceded by a bout of tachycardia with heart rates of 120 to 160 beats per minute.
If syncope occurs the patient should be placed in a recumbent position and given supportive treatment as necessary.
Dizziness, light-headedness or fainting may occur when standing up quickly from a lying or sitting position. Patients should be advised of this possibility and instructed to lie down if these symptoms appear and then sit for a few minutes before standing to prevent re-occurrence.
These adverse events are self-limiting and, in most cases, do not recur after the initial period of therapy or during subsequent titration.
Adverse events reported with terazosin
The most common events were asthenia, palpitations, nausea, peripheral oedema, dizziness, somnolence, nasal congestion/rhinitis and blurred vision/amblyopia.
In addition, the following have been reported: back pain; headache; tachycardia; postural hypotension; syncope; oedema; weight gain; pain in extremities; decreased libido; depression; nervousness; paraesthesia; vertigo; dyspnoea; sinusitis and impotence.
Very rarely urticaria has been reported.
Additional adverse reactions reported in clinical trials or reported during marketing experience but not clearly associated with the use of terazosin include the following: chest pain; facial oedema; fever; abdominal pain; neck pain; shoulder pain; vasodilation; arrhythmia; constipation; diarrhoea;
dry mouth; dyspepsia; flatulence; vomiting; gout; arthralgia; arthritis; joint disorders; myalgia; anxiety; insomnia; bronchitis; epistaxis; flu symptoms; pharyngitis; rhinitis; cold symptoms; pruritis; rash; increased cough; sweating; abnormal vision; conjunctivitis; tinnitus; urinary frequency; urinary tract infection and urinary incontinence primarily reported in post-menopausal women.
At least two cases of severe anaphylactoid reactions have been reported with the administration of terazosin.
Post marketing experience: Thrombocytopenia and priapism have been reported. Atrial fibrillation has been reported: however, a cause and effect relationship has not been established.
Laboratory tests: Small but statistically significant decreases in haematocrit, haemoglobin, white blood cells, total protein and albumin were observed in controlled clinical trials. These laboratory findings suggest the possibility of haemodilution. Treatment with terazosin for up to 24 months had no significant effect on prostate specific antigen (PSA) levels.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard.
4.9. Overdose.
Should administration of terazosin lead to acute hypotension, cardiovascular support is of first importance. Restoration of blood pressure and normalisation of heart rate may be accomplished by keeping the patient in a supine position. If this measure is inadequate, shock should first be treated with volume expanders and, if necessary, vasopressors could then be used. Renal function should be monitored and general supportive measures applied as required. Dialysis may not be of benefit since laboratory data indicate that terazosin is highly protein bound.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: alpha-adrenoreceptor anatagonist ATC code: G04C A03
Use in hypertension
Although the exact mechanism of the hypotensive action is not established, the relaxation of peripheral blood vessels appears to be produced mainly by competitive antagonism of postsynaptic alpha-1-adrenoceptors. Terazosin usually produces an initial gradual decrease in blood pressure followed by a sustained antihypertensive action.
Clinical experience indicates that a 2-5% decrease in total cholesterol plasma concentration and a 3-7% decrease in the combined LDLc + VLDLc fraction plasma concentration from pretreatment values are associated with the administration of therapeutic doses of terazosin.
Use in BPH
Studies suggest that alphai-adrenoreceptor antagonism is useful in improving the urodynamics in patients with chronic bladder obstruction such as in benign prostatic hyperplasia.
The symptoms of BPH are caused mainly by the presence of an enlarged prostate and by the increased smooth muscle tone of the bladder outlet and prostate, which is regulated by alpha-i-adrenergic receptors.
In in-vitro experiments, terazosin has been shown to antagonise phenylephrine-induced contractions of human prostatic tissue. In clinical trials terazosin has been shown to improve the urodynamics and symptomatology in patients with BPH.
5.2. Pharmacokinetic Properties
Absorption
Terazosin is well-absorbed (80-100%). Terazosin has a minimal “first pass” effect and almost the complete dose of terazosin is systematically available. Peak plasma concentrations are reached approximately 1-2 hours after oral dosing in the fasted state. Bioavailability is not significantly affected by food uptake.
Distribution
Approximately 90-94% of terazosin is bound to plasma proteins. Protein binding is independent of total active substance concentrations.
Biotransformation
Main metabolites of terazosin are caused by demethylation and conjugation. Elimination
Approximately 10% and 20% of orally administered terazosin is excreted as unchanged active substance in urine and in faeces, respectively. Approximately 40% of the administered dose of terazosin is eliminated in urine and 60% in faeces. The total elimination half-life is approximately 8-13 hours.
Linearity/non-linearity of pharmacokinetics
After oral dosing of terazosin AUC and Cmax increase in proportion with dose over the recommended dose range (2-10mg).
5.3 Preclinical Safety Data
Carcinogenicity: terazosin has been shown to produce benign adrenal medullary tumours in male rats when administered at a high dose over a long period of time. No such occurrences were seen in female rats or in a similar study in mice. The relevance of these findings with respect to the clinical use of the active substance in man is unknown.
No evidence of a genotoxic effect of terazosin has been reported from in vitro and in vivo investigations of the mutagenic potential of the substance.
6.1. List of Excipients
Lactose monohydrate Maize starch Povidone (K-30) Crospovidone Talc
Magnesium stearate (E572) Yellow iron oxide (E172) Red iron oxide (E172)
6.2. Incompatibilities
Not applicable.
6.3. Shelf-Life
36 months.
6.4. Special Precautions for Storage
Do not store above 25°C. Store in the original package.
6.5. Nature and Contents of Container
Transparent or white opaque PVdC coated PVC film with hard temper aluminium foil blisters in packs of 14, 20 (including samples), 28 (including samples), 30 (including 3 x 10), 50, 84, 100 tablets or a starter pack of (7 x 1 mg, 14 x 2 mg & 7 x 5 mg) tablets.
Not all pack sizes may be marketed
6.6. Instructions for Use, Handling and Disposal
No special requirements.
7. Marketing Authorisation Holder
TEVA UK Limited,
Brampton Road, Hampden Park Eastbourne, BN22 9AG
8.
MARKETING AUTHORISATION NUMBER(S)
PL 00289/0365
AUTHORISATION
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
26/07/2000
10
DATE OF REVISION OF THE TEXT
13/05/2015