Cipalat XR 30 mg, 60 mg XR tablets

CIPALAT XR is indicated for the:

• Treatment of mild to moderate hypertension.
• Prophylaxis of chronic stable angina pectoris.

Posology

Adults: The recommended initial dose is one 30 mg tablet once daily. The dose may be increased according to individual requirements up to a maximum of 90 mg once daily. Titration steps should proceed over a 7 to 14 days period so that the response to each dose level can be assessed before proceeding to higher doses.

Special populations

Patients with Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.

Patients with hepatic impairment: Owing to the duration of action of the formulation, CIPALAT XR should not be administered to patients with hepatic impairment (see section 4.3).

Elderly: A slight alteration of the pharmacokinetics of CIPALAT XR may be seen in the elderly. However, dosage adjustment in these patients is not usually necessary.

Paediatric population: The safety and efficacy of CIPALAT XR in children below 18 years has not been established.

Method of administration: Oral use. CIPALAT XR tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed. Grapefruit juice is to be avoided. It is recommended that each dose of CIPALAT XR should be taken at approximately 24 hours intervals i.e. at the same time each day, preferably in the morning. CIPALAT XR may be taken independently of mealtimes.

Known hypersensitivity to nifedipine or to other dihydropyridines because of the theoretical risk of cross-reactivity or any other ingredient of CIPALAT XR listed in section 6.1. CIPALAT XR must not be used in patients with clinically significant aortic stenosis, in cardiogenic shock, unstable angina or within one month of a myocardial infarction. CIPALAT XR should not be used for the treatment of acute attacks of angina. The safety of CIPALAT XR in malignant hypertension has not been established. CIPALAT XR should not be used for secondary prevention of myocardial infarction. Due to the duration of action of the formulation, CIPALAT XR should not be used in patients with hepatic impairment (see section 4.4). CIPALAT XR should not be administered to patients with a history of gastrointestinal obstruction, oesophageal obstruction or any degree of decreased lumen diameter of the gastrointestinal tract. CIPALAT XR is contraindicated in patients with inflammatory bowel disease. CIPALAT XR should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction by rifampicin. CIPALAT XR is contraindicated in pregnancy and lactation (see section 4.6).

CIPALAT XR tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up. Grapefruit juice inhibits the metabolism of CIPALAT XR. After regular intake of grapefruit juice the blood pressure lowering effect may last for at least 3 days after the last ingestion of grapefruit juice (see section 4.5). Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure. 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 cases of severe aortic stenosis. The following medicines are known to either inhibit or to induce cytochrome P450 3A4 system and may therefore alter the first pass or clearance of nifedipine: Digoxin, phenytoin, quinidine, quinupristin, dalfopristin, cimetidine, rifampicin, diltiazem, cisapride, macrolide antibiotics (e.g., erythromycin), fluoxetine, anti-HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), azole antimycotics (e.g. ketoconazole, itraconazole, fluconazole), nefazodine, tacrolimus, carbamazepine, phenobarbitone and valproic acid. See section 4.5) Upon co-administration with these medicines, the blood pressure should be monitored and, if necessary, a reduction of the CIPALAT XR dose should be considered. CIPALAT XR is contraindicated in pregnancy (see section 4.3 and section 4.6). However, care must be exercised in pregnant women when administering CIPALAT XR in combination with intravenous 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. Safety of CIPALAT XR as tocolytic medicine and in the treatment of hypertension in pregnancy after 20 weeks has not been established. Harm to the foetus cannot be excluded. CIPALAT XR is contraindicated 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). CIPALAT XR is contraindicated in patients with hepatic impairment (see section 4.2 and 4.3). CIPALAT XR may be used in combination with beta-blocking medicines and other antihypertensive medicines but the possibility of an additive effect resulting in postural hypotension should be taken into consideration. CIPALAT XR will not prevent possible rebound effects after cessation of other antihypertensive therapy. CIPALAT XR should not be switched once a patient has been stabilised, without appropriate monitoring. Diabetic patients taking CIPALAT XR may require adjustment of their control. Care should be exercised in dialysis patients with malignant hypertension and irreversible kidney failure with hypovolaemia as a marked fall in blood pressure may occur. A transient increase in blood glucose has been noted. Care must be taken in patients with diabetes mellitus. CIPALAT XR should be used with caution in patients with a poor cardiac reserve. Deterioration of heart failure has occasionally been observed with nifedipine. In single cases obstructive gastrointestinal symptoms have been described without known history of gastrointestinal disorders. Upon swallowing, the biologically inert components of the CIPALAT XR tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell and appears to be the complete tablet and 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 CIPALAT XR to patients, as obstructive symptoms may occur. Bezoars can occur and may require surgical intervention. CIPALAT XR must not be used in patients with Kock pouch (ileostomy after proctocolectomy). When doing barium contrast X-ray, CIPALAT XR may cause false positive effects (e.g. filling defects interpreted as polyp). Excipients: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say 'sodium-free'.

CIPALAT XR is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Medicines that are known to either inhibit or induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of CIPALAT XR (see section 4.4). Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to CIPALAT XR should be monitored and, if necessary, an increase in the CIPALAT XR dose considered. If the dose of CIPALAT XR is increased during co-administration of both medicines, a reduction of the CIPALAT XR dose should be considered when the treatment is discontinued. The extent as well as the duration of interactions should be taken into account when administering CIPALAT XR together with the following medicines: Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of CIPALAT XR is distinctly reduced and thus its efficacy weakened. The use of CIPALAT XR 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 CIPALAT XR dose considered (see sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a medicine interaction between nifedipine and the medicine(s) listed have been undertaken, thus far. Erythromycin: Erythromycin is known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicines. Therefore, the potential for an increase of CIPALAT XR plasma concentrations upon co-administration of both medicines cannot be excluded. Amprenavir, indinavir, nelfinavir, ritonavir, saquinavir: A clinical study investigating the potential of an interaction between CIPALAT XR and indinavir, nelfinavir, ritonavir or saquinavir has not yet been performed. Medicines of this class are known to inhibit the cytochrome P450 3A4 system. In addition, indinavir and ritonavir have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of CIPALAT XR. When administered together with CIPALAT XR, a substantial increase in plasma concentrations of CIPALAT XR due to a decreased first pass metabolism and a decreased elimination cannot be excluded. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. Ketoconazole, itraconazole, fluconazole: Medicines of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with CIPALAT XR a substantial increase in systemic bioavailability of CIPALAT XR due to decreased first pass metabolism cannot be excluded. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. Fluoxetine: Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of CIPALAT XR. Therefore an increase of CIPALAT XR plasma concentrations upon co-administration of both medicines cannot be excluded. When fluoxetine is given together with CIPALAT XR, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. Nefazodone: A clinical study investigating the potential of an interaction between CIPALAT XR and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicines. Therefore, an increase of CIPALAT XR plasma concentrations upon co-administration of both medicines cannot be excluded. When nefazodone is given together with CIPALAT XR, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. Quinupristin / Dalfopristin: Simultaneous administration of quinupristin/dalfopristin and CIPALAT XR may lead to increased plasma concentrations of CIPALAT XR. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. 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 CIPALAT XR plasma concentrations cannot be excluded. Cimetidine: Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentration of CIPALAT XR and may potentiate the antihypertensive effect. Cisapride: Simultaneous administration of cisapride and CIPALAT XR may lead to increased plasma concentrations of CIPALAT XR. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the CIPALAT XR dose considered. Phenytoin: Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of CIPALAT XR is reduced and thus its efficacy weakened. When both medicines are concomitantly administered, the clinical response of CIPALAT XR should be monitored and, if necessary, an increase of the CIPALAT XR dose considered. If the dose of CIPALAT XR is increased during co-administration of both medicines, a reduction of the CIPALAT XR dose should be considered when the treatment with phenytoin is discontinued. Carbamazepine: As carbamazepine has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in CIPALAT XR plasma concentrations and hence an increase in efficacy cannot be excluded. Phenobarbitone: As phenobarbitone has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in CIPALAT XR plasma concentrations and hence an increase in blood levels cannot be excluded. Effects of CIPALAT XR on other medicines: CIPALAT XR may increase the blood pressure lowering effect on concomitant applied antihypertensives, such as:

• Diuretics
• u03b2-blockers
• ACE-inhibitors
• AT1-antogonists/Angiotensin 1 receptor blockers
• Other calcium antagonists
• u03b1-adrenergic blocking agents
• PDE5 inhibitors
• u03b1-methyldopa

Pregnancy: CIPALAT XR is contraindicated during pregnancy (see section 4.3). In animal studies, nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity when administered during any stage of pregnancy and decreased neonatal survival after birth. Co-administration of CIPALAT XR with I.V. magnesium sulphate may cause an excessive fall in blood pressure which could harm both mother and foetus.

Breastfeeding: CIPALAT XR is contraindicated during breastfeeding (see section 4.3). Nifedipine is excreted in the breast milk.

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.

Reactions to CIPALAT XR, 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.

The following adverse drug reactions (ADRs) can occur:

Tabulated list of adverse reactions

MedDRA system organ class Frequency Side effects

Immune system disorders Less frequent Allergic reaction, allergic oedema/angioedema (incl. larynx oedema*), pruritus, urticaria, rash

Psychiatric disorders Less frequent Anxiety reactions, sleep disorders

Nervous system disorders Frequent Headache

Less frequent Vertigo, migraine, dizziness. tremor, paraesthesia/dysaesthesia, somnolence

Eye disorders Frequent Eye pain

Less frequent: Visual disturbances, amblyopia

Cardiac disorders Less frequent Tachycardia, palpitations, chest pain (angina pectoris)

Vascular disorders Frequent Oedema (incl. peripheral oedema), vasodilatation

Less frequent Hypotension, syncope

Respiratory, thoracic and mediastinal disorders Less frequent Nosebleed, nasal congestion

Gastrointestinal disorders Frequent Constipation

Less frequent Gastrointestinal and abdominal pain, vomiting, nausea, dyspepsia, flatulence, dry mouth, gingival hyperplasia, gastroesophageal reflux, gastroesophageal sphincter insufficiency.

Hepato - biliary disorders Less frequent: Transient increase in liver enzymes

Skin and subcutaneous tissue disorders Less frequent Erythema, palpable purpura

Musculoskeletal and connective tissue disorders Less frequent Muscle cramps, joint swelling, arthralgia, myalgia

Renal and urinary disorders Less frequent: Polyuria, dysuria

Reproductive system and breast disorders Less frequent Erectile dysfunction

General disorders and administration site conditions Frequent: Feeling unwell

Less frequent: Unspecific pain, chills

* = may result in life-threatening outcome

Post-marketing experience: The ADRs for which a frequency could not be estimated (frequency unknown), are listed below:

MedDRA system Organ Class Side effects

Blood and lymphatic system disorders Agranulocytosis, Leucopenia

Immune system disorders Anaphylactic/anaphylactoid reaction

Endocrine disorders Gynaecomastia

Metabolism and nutrition disorders Hyperglycaemia

Nervous system disorders Hypoaesthesia

Respiratory, thoracic and mediastinal disorders Dyspnoea, Pulmonary oedema**

Gastrointestinal disorders Bezoar, Dysphagia, Intestinal obstruction, Intestinal ulcer, Vomiting

Hepato-biliary disorders Jaundice

Skin and subcutaneous tissue disorders Toxic epidermal necrolysis, Photosensitivity allergic reaction

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

Description of selected adverse reactions: 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website, or to Cipla Medpro (Pty) Ltd. by email: [email protected] or telephone: 080 222 6662 (toll free).

Symptoms: The following symptoms are observed in cases of severe nifedipine intoxication: Flushing, headaches, severe hypotension, increase or decrease in heart rate, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema and unconsciousness to the point of coma have been observed.

Treatment: Particularly in cases of intoxication with prolonged release products like CIPALAT XR elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance. Treatment is symptomatic and supportive. Bradycardiac heart rhythm disturbances may be treated symptomatically with u00df-sympathomimetics and in life-threatening bradycardiac disturbances of heart rhythm, temporary pacemaker therapy is advisable. Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10 u2013 20 mL of a 10 % calcium gluconate solution administered intravenously and repeated if necessary). As a result, the serum calcium may reach the upper normal to slightly elevated levels. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or norepinephrine (noradrenaline) may be administered additionally. The dosage of these medicines is determined solely by the effect obtained. Haemodialysis serves no purpose as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution). Additional liquid or volume must be administered with caution to avoid cardiac overload.