Bayer Limited

Adalat 10 mg soft capsules

Each capsule contains 10 mg nifedipine.

Excipients: Sunset yellow (E110) 0.27mg per capsule

For full list of excipients, see section 6.1.

Capsule, soft.

Orange, gelatin ovoid capsules containing a yellow viscous liquid.

For the management of chronic stable angina pectoris, the treatment of Raynaud's syndrome and essential hypertension.

• For patients suffering from essential hypertension or chronic stable angina pectoris, and treated with fast release forms of nifedipine (Adalat 5 mg and 10 mg capsules), a dose dependent increase in the risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur.

• Due to this, Adalat 5 mg and 10 mg capsules should only be used for treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.

Method of administration

Oral Use

Dosage regimen

As far as possible the treatment must be tailored to the needs of the individual according to the severity of the disease and the patient's response.

Depending on the clinical picture in each case, the basic dose must be introduced gradually

Dose titration is recommended for hypertensives with severe cerebrovascular disease and for patients, who because of low body weight or multiple therapies with other antihypertensive drugs, are likely to have an excessive reaction to nifedipine. In addition, patients in whom side effects in response to the nifedipine treatment make a finer dose adjustment desirable should be individually stabilized with Adalat 5 mg capsule.

Unless otherwise prescribed, the following dosage guidelines are recommended for adults:

• In coronary heart disease:

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg, the dose should be increased individually.

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg the dose should be increased individually.

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg, the dose should be increased individually.

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see “interaction with other medicinal products and other forms of interaction").

Duration of Treatment

The attending doctor will determine the duration of use.

Due to their pronounced antiischemic and antihypertensive action, Adalat capsules should be discontinued gradually, particularly when high doses are used.

Administration

As a rule Adalat capsules are swallowed whole with a little liquid, irrespective of meal times. Grapefruit juice is to be avoided (see “interaction with other medicinal products and other forms of interaction“).).

Patients taking 20 mg unit doses of immediate release formulations such as Adalat 5 mg capsule or Adalat 10 mg capsule should allow an interval of at least 2 h between doses.

Additional information on special populations

Children and adolescents

Geriatric patients

Patients with hepatic impairment

In patients with impaired liver function, careful monitoring and, in severe cases, a dose reduction may be necessary.

Patients with renal impairment

Based on pharmacokinetic data no dosage adjustment is required in patients with renal impairment (see “Pharmacokinetic properties”)

Adalat 10 mg must not be administered to patients with known hypersensitivity to nifedipine or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients.

Adalat 10mg must not be administered to women during pregnancy or to nursing mothers.

There are no safety and efficacy data from well-controlled studies in pregnant women (see“Pregnancy and lactation”).

Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects when administered during and after the period of organogenesis. (see “Preclinical safety data”)

(See Sections 4.4. Special warnings and precautions for use, 4.6. Pregnancy and lactation and 5.3. Preclinical safety data).

Adalat 10 mg must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina pectoris, or during or within 4 weeks of an acute myocardial infarction.

Adalat 10 mg should not be used for the treatment of acute attacks of angina.

The safety of Adalat 10 mg in malignant hypertension has not been established.

Adalat 10 mg should not be used for secondary prevention of myocardial infarction.

Adalat 10 mg must not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (See Section 4.5, Interaction with other medicinal products and other forms of interactions).

Adalat 10 mg is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker, preferably over 8-10 days.

Adalat 10 mg may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Adalat 10 mg will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm HG), in cases of manifest heart failure and in the case of severe aortic stenosis.

Treatment with short-acting nifedipine may induce an exaggerated fall in blood pressure and reflex tachycardia, which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.

As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.

In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.

The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.

There are no safety and efficacy data from well-controlled studies in pregnant women (See section 4.6. Pregnancy and lactation).

Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects (See Section 5.3. Preclinical safety data) when administered during and after the period of organogenesis.

From the clinical evidence available a specific prenatal risk has not been identified. Although an increase in perinatal asphyxia, caesarean deliveries as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.

The available information is inadequate to rule out adverse drug effects on the unborn and newborn child.

Whilst nifedipine is contra-indicated in pregnancy, particular care must be exercised when administering nifedipine in combination with i.v. magnesium sulphate to pregnant women.

In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.

Adalat 10 mg should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

At doses higher than those recommended, there is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease, in particular after myocardial infarction.

Ischaemic pain has been reported in a small proportion of patients within 30 to 60 minutes of the introduction of Adalat 10 mg therapy. Although a “steal” effect has not been demonstrated, patients experiencing this effect should discontinue Adalat 10 mg.

The use of Adalat 10 mg in diabetic patients may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (See Section 4.5, Interaction with other medicinal products and other forms of interaction).

Drugs which are moderate inhibitors of the cytochrome P450 3 A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

-macrolide antibiotics (e.g., erythromycin)

-anti-HIV protease inhibitors (e.g., ritonavir)

-azole antimycotics (e.g., ketoconazole)

-the antidepressants, nefazodone and fluoxetine

-quinupristin/dalfopristin

-valproic acid

-cimetidine

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered (See Section 4.5, Interaction with other medicinal products and other forms of interactions).

Adalat 10mg capsules contain the excipient sunset yellow (E110) which may cause allergic reactions.

Drugs that affect nifedipine

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (See Sections 4.4. Special warnings and precautions for use).

The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:

Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (See Section 4.3. Contraindications).

Upon co-administration of weak to moderate inhibitors of the cytochrome P450 3A4 system (listed immediately below), the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (See Section 4.2 Posology and method of administration and see section 4.4. Special warnings and precautions for use). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.

Macrolide antibiotics (e.g., erythromycin):

Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (See section 4.4. Special warnings and precautions for use).

Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP3A4 inhibition.

Anti-HIV protease inhibitors (e.g., ritonavir):

Drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded (See section 4.4. Special warnings and precautions for use).

Azole anti-mycotics (e.g., ketoconazole):

Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded (See section 4.4. Special warnings and precautions for use).

Fluoxetine:

Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (See section 4.4. Special warnings and precautions for use).

Nefazodone:

Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase in nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (See section 4.4. Special warnings and precautions for use).

Quinupristin/dalfopristin and cisapride:

Simultaneous administration of quinupristin/dalfopristin and nifedipine, or cisapride and nifedipine, may lead to increased plasma concentrations of nifedipine (See section 4.4. Special warnings and precautions for use).

Valproic acid:

As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker, nimodipine, due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded (See section 4.4. Special warnings and precautions for use).

Cimetidine:

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (See section 4.4. Special warnings and precautions for use).

Further studies

Cisapride

Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.

Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbital: phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When both drugs are administered concomitantly, the clinical response to nifedipine should be monitored and, if necessary, an increase of the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued.

No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbital. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker, nimodipine, due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded.

Effects of nifedipine on other drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as:

-diuretics

-beta-blockers

-ACE-inhibitors

-Angiotensin 1 (AT1) receptor-antagonists

-other calcium antagonists

-alpha-adrenergic blocking agents

-PDE5 inhibitors

-alpha-methyldopa

When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.

Digoxin:

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin.

Quinidine:

When nifedipine and quinidine have been administered simultaneously, lowered quinidine levels, or after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine, have been observed in individual cases. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon co-administration of both drugs, while others did not observe an alteration in the pharmacokinetics of nifedipine.

Therefore the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with nifedipine. If necessary, the dose of nifedipine should be decreased.

Tacrolimus:

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Drug food interactions

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice.

Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (See Section 4.2 Dosage and method of administration).

Drugs shown not to interact with nifedipine

The following drugs have been shown to have no effect on the pharmacokinetics of nifedipine when administered concomitantly: ajmaline, aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone, talinolol and triamterene hydrochlorothiazide.

Other forms of interaction

Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.

Pregnancy

Adalat 10 mg is contra-indicated during pregnancy. (See Section 4.3. Contraindications).

Adalat 10 mg should not be used by women who intend to get pregnant in the near future.

The safety of Adalat 10 mg for use in human pregnancy has not been established.

There are no adequate and well controlled studies in pregnant women..

In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity (see “Preclinical safety data”).

Evaluation of experimental animal studies has shown reproductive toxicity consisting of embryotoxicity and teratogenic effects at maternally toxic doses.

Lactation

Adalat 10 mg is contra-indicated in breastfeeding. Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

In-vitro fertilisation

In single cases of in vitro fertilisation calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Reactions to the drug, which vary in intensity from individual to individual, can impair the ability to drive or to operate machinery. This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n=2,661; placebo n=1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n=3,825; placebo n=3,840) are listed below: ADRs listed under “common” were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).

The frequencies of ADRs reported with nifedipine are summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1,000). The ADRs identified only during the ongoing postmarketing surveillance, and for which a frequency could not be estimated, are listed under “Not known”.

¹ = may result in life-threatening outcome.

In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.

Symptoms

The following symptoms are observed in cases of severe nifedipine intoxication:

Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardiac/bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Treatment

As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular conditions have priority.

After oral ingestion, thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. In case of intoxication with nifedipine, elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

Haemodialysis serves no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).

Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered slowly i.v.and repeated if necessary). As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.

Symptomatic bradycardia may be treated with beta-sympathomimetics, and in life- threatening bradycardiac disturbances of heart rhythm, temporary pacemaker therapy may be advisable.

Additional liquid or volume must be administered with caution because of the danger of overloading the heart.

ATC code: C08 CA05

Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. As a specific and potent calcium antagonist, nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. The main action of Adalat 10 mg is to relax arterial smooth muscle both in the coronary and peripheral circulation.

In angina pectoris, Adalat 10 mg relaxes peripheral arteries so reducing the load on the left ventricle. Additionally, Adalat 10 mg dilates submaximally both clear and pre-stenotic coronary arteries, and stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.

Adalat 10 mg reduces the frequency of painful attacks and the ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.

Adalat 10 mg causes a reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Adalat 10 mg has little or no effect on blood pressure.

In Raynaud's syndrome nifedipine can prevent or reduce the occuring digital vasospasm.

Absorption

After oral administration nifedipine is immediately and almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (Adalat capsules) is 45 - 56% owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 minutes. Simultaneous food intake leads to delayed, but not reduced absorption.

Distribution

Nifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.

Biotransformation

After oral administration nifedipine is metabolised in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5 - 15% via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1%) in the urine.

Elimination

The terminal elimination half-life is 1.7 to 3.4 hours. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In cases of impaired liver function the elimination half-life is distinctly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases.

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproduction toxicology

Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans (See Section 4.6. Pregnancy and lactation).

Glycerol

Purified water

Saccharin sodium

Peppermint oil

Macrogol 400

The capsule shell contains:

Gelatin

Glycerol (85 per cent)

Titanium dioxide (E171)

Sunset yellow (E110)

Not applicable.

3 years.

Store in the original package. Keep blister in the outer carton. Do not store above 30°C.

Blister strips of polypropylene foil backed with aluminium foil: 90 capsules.

No special requirements.

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

PA1410/25/2

Date of first authorisation: 25/05/1977

Date of last renewal: 25/05/2007

December 2011