NIDEF Prolonged release tablet Ref.[7009] Active ingredients: Nifedipine

Nidef/Nifedipine Prolonged Released Tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

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 sulphate, 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, refer to 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 oral absorption of small amounts of nifedipine 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.

Nidef/Nifedipine Prolonged Released Tablets 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. Nidef/Nifedipine Prolonged Released Tablets will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Nidef/Nifedipine Prolonged Released Tablets 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 Nidef/Nifedipine Prolonged Released Tablets 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).

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.

As the outer membrane of the Nidef/Nifedipine Prolonged Released Tablets may not be digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient’s stools. Also, as a result of this, care should be exercised when administering Nidef/Nifedipine Prolonged Released Tablets to patients, as obstructive symptoms may occur. Bezoars may occur in very rare cases and may require surgical intervention.

In single cases obstructive symptoms have been described without known history of gastrointestinal disorders.

A false positive effect may be experienced when performing a barium contrast x-ray.

For use in special populations see section 4.2.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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.

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 contra-indicated (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 section 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 ß-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 level 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 are 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 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 may be increased. After regular intake of grapefruit juice this effect may last for at least 3 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 cause increase spectrophotometric values of urinary vanillyl-mandelic acid, falsely. However, HPLC measurements are unaffected.

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, fetotoxicity and teratogenicity (see section 5.3).

There are no adequate and 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 has 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 breastfeeding 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 fertilization 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 fertilization, 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 (see section 4.8). 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-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 postmarketing surveillance, and for which a frequency could not be estimated, are listed under “Not known”.

Blood and Lymphatic System Disorders

Not Known: Agranulocytosis, Leucopenia

Immune System Disorders

Uncommon: Allergic reaction, Allergic oedema/angioedema (incl. larynx oedema*)

Rare: Pruritus, Urticaria, Rash

Not Known: Anaphylactic/Anaphlactic/anaphylactoid reaction

Psychiatric Disorders

Uncommon: Anxiety reactions, Sleep disorders

Metabolism and Nutrition Disorders

Not Known: Hyperglycaemia

Nervous System Disorders

Common: Headache

Uncommon: Vertigo, Migraine, Dizziness, Tremor

Rare: Par-/Dysaesthesia

Not Known: Hypoaesthesia, Somnolence

Eye Disorders

Uncommon: Visual disturbances

Not Known: Eye pain

Cardiac Disorders

Uncommon: Tachycardia, Palpitations

Not Known: Chest pain (Angina pectoris)

Vascular Disorders

Common: Oedema (incl. Peripheral oedema), Vasodilatation

Uncommon: Hypotension, Syncope

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon: Nosebleed, Nasal congestion

Not Known: Dyspnoea, Pulmonary oedema**

Gastrointestinal Disorders

Common: Constipation

Uncommon: Gastrointestinal and abdominal pain, Nausea, Dyspepsia, Flatulence, Dry mouth

Rare: Gingival hyperplasia

Not Known: Bezoar, Dysphagia, Intestinal obstruction, Intestinal ulcer, Vomiting, Gastroesophageal sphincter insufficiency

Hepatobiliary Disorders

Uncommon: Transient increase in liver enzymes

Not Known: Jaundice

Skin and Subcutaneous Tissue Disorders

Uncommon: Erythema

Not Known: Toxic Epidermal Necrolysis, Photosensitivity allergic reaction, Palpable purpura

Musculoskeletal and Connective Tissue Disorders

Uncommon: Muscle cramps, Joint swelling

Not Known: Arthralgia, Myalgia

Renal and Urinary Disorders

Uncommon: Polyuria, Dysuria

Reproductive System and Breast Disorders

Uncommon: Erectile dysfunction

General Disorders and Administration Site Conditions

Common: Feeling unwell

Uncommon: Unspecific pain, Chills

* = may result in life-threatening outcome
** = cases have been reported when used as tocolytic during pregnancy (see section 4.6)

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.

Not applicable.