4.1. Therapeutic indications

Valni 20 Retard tablets are indicated for the following:

(i) Hypertension

(ii) The prophylaxis of chronic stable angina pectoris

4.2. Posology and method of administration

Posology

Adults

The recommended dose is one tablet (20 mg) every 12 hours. The dosage may be increased up to 40 mg every 12 hours to achieve the desired effect.

Paediatric population

The safety and efficacy of nifedipine in children under the age of 18 years has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1.

Elderly

There are no special dosage requirements for the elderly, however, the pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Hepatic Impairment

Patients with hepatic dysfunction must be carefully monitored when treatment is commenced as Nifedipine is primarily metabolised in the liver. If hepatic function is impaired, the dosage requirements of nifedipine should be established before use of Valni 20 Retard.

Renal Impairment

Dosage adjustments should not be required for patients with renal impairment.

Treatment with Valni 20 Retard may be continued long term.

Method of Administration

Oral administration.

It is recommended that these tablets are swallowed with a glass of water. These tablets must be swallowed whole and not broken or chewed.

These tablets should not be taken with grapefruit juice (see section 4.5).

4.3. Contraindications

Hypersensitivity to nifedipine, any of the excipients listed in section 6.1. or other dihydropyridines because of the theoretical risk of cross reactivity.

Nifedipine should not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.

Nifedipine should not be used for the treatment of acute attacks of angina.

The safety of nifedipine in malignant hypertension has not been established.

Nifedipine should not be used for secondary prevention of myocardial infarction.

Owing to the duration of action of the formulation, Nifedipine should not be administered to patients with hepatic impairment.

Nifedipine should not be administered to patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.

Nifedipine must not be used in patients with a Kock pouch (ileostomy after proctocolectomy).

Nifedipine is contra-indicated in patients with inflammatory bowel disease or Crohn's disease.

Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).

4.4. Special warnings and precautions for use

Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure and care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg).

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.6).

Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus. For further information regarding use in pregnancy, see section 4.6.

Nifedipine is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known (see section 4.6).

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

Nifedipine 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. Nifedipine will not prevent possible rebound effects after cessation of other antihypertensive therapy.

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

Diabetic patients taking nifedipine may require adjustment of their diabetic treatment.

In dialysis patients with malignant hypertension and hypovolaemia, a significant 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).

Drugs which are known inhibitors of the cytochrome P450 3A4 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.

For use in special populations see section 4.2.

Excipient(s) with known effect

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

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 section 4.4).

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).

Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see sections 4.2 and 4.4). 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.

Drugs increasing nifedipine exposure:

• Macrolide antibiotics (e.g. erythromycin)

• Anti-HIV protease inhibitors (e.g. ritonavir)

• Azole anti-mycotics (e.g. ketoconazole)

• Fluoxetine

• Nefazodone

• Quinupristin/Dalfopristin

• Cisapride

• Valproic acid

• Cimetidine

• Diltiazem

Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in 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 is discontinued.

Drugs decreasing nifedipine exposure:

• Rifampicin (see above)

• phenytoin

• carbamazepine

• phenobarbital

Effects of nifedipine on other drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.

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 subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced.

Quinidine

Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose is recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.

Tacrolimus

Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data 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).

Other forms of interaction

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine (see section 4.4).

In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).

There are no adequate, well-controlled studies in pregnant women.

From the clinical evidence available, a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, 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. Therefore, any use in pregnancy requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.

Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine, have been used as a tocolytic agent during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.

Breast-feeding

Nifedipine is excreted in the breast milk. The nifedipine concentration in the milk is almost comparable with mother serum concentration. For immediate release formulations, it is proposed to delay breast-feeding or milk expression for 3 to 4 hours after drug administration to decrease the nifedipine exposure to the infant (see section 4.4).

Fertility

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.

4.7. Effects on ability to drive and use machines

Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery (see section 4.8). This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.

4.8. Undesirable effects

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-containing products 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 post-marketing surveillance, and for which a frequency could not be estimated, are listed under “Not known”.

System Organ Class (MedDRA)

Common

Uncommon

Rare

Not Known

Blood and Lymphatic System Disorders

Agranulocytosis

Leucopenia

Immune System Disorders

Allergic reaction

Allergic oedema / Angioedema (incl. larynx oedema*)

Pruritus

Urticaria

Rash

Anaphylactic/ Anaphylactoid reaction

Metabolism and Nutrition Disorders

Hyperglycaemia

Psychiatric Disorders

Anxiety reactions

Sleep disorders

Depression

Nervous System Disorders

Headache

Migraine

Vertigo

Dizziness

Tremor

Dysaesthesia

Paraesthesia

Lethargy

Hypoaesthesia

Somnolence

Eye disorders

Visual disturbances

Eye pain

Cardiac Disorders

Tachycardia

Palpitations

Chest pain (Angina pectoris)

Vascular Disorders

Oedema (incl. peripheral oedema)

Vasodilatation

Hypotension

Syncope

Respiratory, Thoracic and Mediastinal Disorders

Nasal congestion

Nosebleed

Dyspnoea

Pulmonary oedema**

Gastrointestinal Disorders

Constipation

Gastrointestinal and abdominal pain

Dyspepsia

Flatulence

Dry mouth

Nausea

Gingival hyperplasia

Vomiting

Bezoar

Dysphagia

Intestinal obstruction

Intestinal ulcer

Gastroesophageal sphincter insufficiency

Hepatobiliary Disorders

Transient increase in liver enzymes

Jaundice

Skin and Subcutaneous Tissue Disorders

Erythema

Toxic Epidermal Necrolysis

Photosensitivity

Allergic reaction

Palpable purpura

Musculoskeletal and Connective Tissue Disorders

Muscle cramps

Joint swelling

Myalgia

Arthralgia

Renal and Urinary Disorders

Dysuria

Polyuria

Increased frequency of micturition

Reproductive System and Breast Disorders

Erectile dysfunction

General Disorders and Administration Site Conditions

Feeling unwell

Unspecific pain

Chills

* = may result in life-threatening outcome

**cases have been reported when used as tocolytic during pregnancy (see section 4.6)

Exacerbation of angina pectoris may occur frequently at the start of treatment with short acting formulations of nifedipine. The occurrence of myocardial infarction has been described although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.

Gingival hyperplasia and, in older men, gynaecomastia have been reported but these are usually reversible on drug withdrawal. Hypersensitivity reactions such as skin rashes and abnormalities of liver function have occurred. These symptoms disappear upon discontinuation of nifedipine.

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

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Treatment

As far as treatment is concerned, elimination of nifedipine 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. Particularly in the cases of intoxication with slow release nifedipine formulations such as Nifedipine Retard. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

The benefit of gastric decontamination is uncertain.

1. Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.

Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.

2. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.

3. Consider further doses of activated charcoal (alternatively ipecacuanha) every 4 hours, if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulphate).

4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.

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 (10-20ml of a 10% calcium gluconate solution administered intravenously over 5-10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. 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 atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required.

Additional fluids should be administered with caution to avoid cardiac overload.