Nicardipine Hydrochloride

Registered South African indications:

• Acute life-threatening hypertension, particularly in the event of
  - Malignant arterial hypertension / hypertensive encephalopathy
  - Aortic dissection, when short acting beta-blocker therapy is not suitable, or in combination with a beta-blocker when beta-blockade alone is not effective
  - Severe pre-eclampsia, when other intravenous antihypertensive medicines are not recommended or are contraindicated
• Postoperative hypertension

Registered South African contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients
• Mitral valve stenosis and severe aortic stenosis including aortic valve stenosis
• Compensatory hypertension, i.e., in case of an arteriovenous shunt or aortic coarctation
• Unstable angina
• Within 8 days after myocardial infarction
• Patients with rare hereditary problems of fructose intolerance should not receive this medicine

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Severe aortic stenosis
• Compensatory hypertension, i.e. in case of an arteriovenous shunt or aortic coarctation
• Unstable angina
• Within 8 days after myocardial infarction
• Patients with rare hereditary problems of fructose intolerance should not take this medicine

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Rapid pharmacologic reductions in blood pressure

• May produce systemic hypotension and reflex tachycardia. Consider decreasing the dose by half or stopping the infusion if either occurs

Bolus or uncontrolled intravenous administration

• Not recommended as it can increase the risk of serious hypotension, especially in the elderly, children, those with renal or hepatic impairment, and during pregnancy

Cardiac failure

• Use nicardipine with caution in patients with congestive heart failure or pulmonary oedema, especially if receiving concomitant beta-blockers, as worsening of cardiac insufficiency may occur

Ischaemic cardiovascular disease

• Nicardipine is contraindicated in unstable angina and immediately following myocardial infarction
• Use nicardipine cautiously in patients with suspected coronary ischemia as increased angina frequency or severity may occur

Pregnancy

• There is a risk of severe maternal hypotension and potentially fatal foetal hypoxia. Concomitant use of nicardipine with magnesium sulphate is contraindicated (South African recommendations)
• Due to risks of severe maternal hypotension and potentially fatal foetal hypoxia, blood pressure should be decreased progressively and monitored closely. Caution is needed if magnesium sulphate is used concomitantly (Recommendations in other jurisdictions)

Patients with history of hepatic dysfunction or impaired hepatic function

• Rare cases of abnormal hepatic function linked to nicardipine use have been reported. Monitor patients with a history of hepatic dysfunction or impaired hepatic function

Patients with portal hypertension

• High doses of intravenous nicardipine may worsen portal vein hypertension and portal-systemic collateral blood flow in cirrhotic patients

Patients with pre-existing elevated intracranial pressure

• Monitor intracranial pressure to calculate cerebral perfusion pressure

Patients with stroke

• Nicardipine should not be used with a recent history of stroke (South African recommendations)
• Use nicardipine with caution in patients with acute cerebral infarction. Hypertensive episodes associated with stroke do not indicate the need for emergency antihypertensive therapy unless acute hypertension affects treatment options or causes life-threatening end-organ damage (Recommendations in other jurisdictions)

Combination with beta-blockers

• Caution is required when using nicardipine with beta-blockers in patients with decreased cardiac function, with beta-blocker dosage tailored to the clinical situation

Injection site reactions

• Infusion site reactions can occur, especially with prolonged administration. Change the infusion site if irritation is suspected, and consider using a central venous line or greater dilution to reduce the risk

Paediatric population

• The safety and efficacy of intravenous nicardipine in infants or children have not been established. Special care is required in this population

Effects on ability to drive and use machines

• Nicardipine has no or negligible influence on the ability to drive and use machines

Additional South African recommendations

Excipient warnings

• Product contains sorbitol. Patients with rare hereditary problem of fructose intolerance should not be given nicardipine

Forms avail. in SA and covered in this monograph: inf

South African registered indications and dosages

Nicardipine hydrochloride should only be administered by medical practitioners experienced in haemodynamic management and only be used in intensive care, high care and interoperative settings. Blood pressure and heart rate must be continuously monitored

Acute life-threatening hypertension, particularly in the event of
- Malignant arterial hypertension / hypertensive encephalopathy
- Aortic dissection, when short acting beta-blocker therapy is not suitable, or in combination with a beta-blocker when beta-blockade alone is not effective
- Severe pre-eclampsia, when other intravenous antihypertensive medicines are not recommended or are contraindicated
Postoperative hypertension

• IV: Initial: Start with continuous administration at a rate of 3-5mg/hr for 15min; Increase rate by increments of 0.5 or 1mg every 15 min; Maintenance: Once target pressure is reached, reduce dose progressively, usually to between 2 and 4mg/hr, to maintain therapeutic efficacy; Max infusion rate: Should not exceed 15mg/hr

---

The speed of administration must be accurately controlled using an electronic syringe driver or a volumetric pump. Blood pressure and heart rate must be monitored at least every 5 minutes during the infusion, and then until vital signs are stable, but at least for 12 hours after the end of the administration of nicardipine hydrochloride

---

The antihypertensive effect will depend on the administered dose. The dosage regimen to achieve the desired blood pressure can vary depending on the targeted blood pressure, the response of the patient, and the age or status of the patient

---

Transition to an oral antihypertensive medicine
Discontinue nicardipine hydrochloride or titrate downward while appropriate oral therapy is established. When an oral antihypertensive medicine is being instituted, consider the lag time of onset of the oral medicine’s affect. Continue blood pressure monitoring until desired effect is achieved

---

Method of administration: Nicardipine hydrochloride should be administered by continuous intravenous infusion only. Unless given by a central venous line, dilute to a concentration of 0.1-0.2mg/ml before use. See additional prescribing points for Incompatibilities and special handling

---

Pregnancy (severe pre-eclampsia): The safety and efficacy have not been established. A syndrome of high blood pressure, fluid accumulation in the tissues and protein in the urine that becomes apparent in the second half of pregnancy. Pre-eclampsia is primarily a placental disorder with damage to the inner lining of placental blood vessels

• The safety and efficacy in low birth weight infants, new-borns, nursing infants, infants and children has not been established

Pregnancy 

South African recommendations

• Caution
• Limited pharmacokinetic data have shown that nicardipine hydrochloride does not accumulate and has a low placental transfer. In clinical practice the use of nicardipine hydrochloride during the first two trimesters in a limited number of pregnancies has not revealed any malformities or particular foetotoxic effect to date
• The use of nicardipine hydrochloride for severe pre-eclampsia during the third trimester of pregnancy could produce a tocolytic effect

Recommendations in other jurisdictions

• Caution
• Limited pharmacokinetic data have shown that nicardipine i.v. does not accumulate and has a low placental transfer. In clinical practice, the use of nicardipine during the first two trimesters in a limited number of pregnancies has not revealed any malformative or particular foetotoxic effect to date
• The use of nicardipine for severe pre-eclampsia during the third trimester of pregnancy could potentially produce an undesirable tocolytic effect which could potentially interfere with the spontaneous induction of labour
• Acute pulmonary oedema has been observed when nicardipine has been used as tocolytic during pregnancy, especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists
• Nicardipine should not be used in multiple pregnancies or in pregnant women with compromised cardio-vascular condition, except if there is no other acceptable alternative

Breastfeeding

South African recommendations

• Caution; not recommended
• Nicardipine hydrochloride and its metabolites are excreted in human milk. Mother on treatment with nicardipine hydrochloride must not breastfeed their babies

Recommendations in other jurisdictions

• Caution; not recommended
• Nicardipine and its metabolites are excreted in human milk at very low concentrations. There is insufficient information on the effects of nicardipine in newborns/infants. Nicardipine should not be used during breastfeeding

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

South African recommendations

• Caution; dose adjustment recommended
  Lower dose regimen in patients with renal impairments

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Nicardipine should be used with particular caution in these patients. In some patients with moderate renal impairment, a significantly lower systemic clearance and higher area under the curve (AUC) have been observed. Therefore, it is recommended to use the same dose regimens as for elderly patients in patients with renal impairment: Provide a continuous infusion of nicardipine starting at the dose of 1-5mg/hr, depending on the blood pressure and clinical situation. After 30 minutes, depending on the effect observed, the rate should be increased or decreased by increments of 0.5mg/hr. The rate should not exceed 15mg/hr

South African recommendations

• Caution; dose adjustment recommended
  Nicardipine should be used with caution in these patients. Since nicardipine is metabolised in the liver, lower dose regimen in patients with impaired liver function

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Nicardipine should be used with particular caution in these patients. Since nicardipine is metabolized in the liver, it is recommended to use the same dose regimens as for elderly patients in patients with impaired liver function or reduced hepatic blood flow: Provide a continuous infusion of nicardipine starting at the dose of 1-5mg/hr, depending on the blood pressure and clinical situation. After 30 minutes, depending on the effect observed, the rate should be increased or decreased by increments of 0.5mg/hr. The rate should not exceed 15mg/hr

South African recommendations

• Caution; no dose adjustment recommended
  The safety and efficacy in patients over 65 years has not been established

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Clinical studies of nicardipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects
  Elderly patients may be more sensitive to nicardipine effects because of impaired renal and/or hepatic function. It is recommended to provide a continuous infusion of nicardipine starting at the dose of 1-5mg/hr, depending on the blood pressure and clinical situation. After 30 minutes, depending on the effect observed, the rate should be increased or decreased by increments of 0.5mg/hr. The rate should not exceed 15mg/hr

Blood and the Lymphatic System Disorders

Not known

• Thrombocytopenia

Metabolism and Nutrition Disorders

Not known

• Hypophosphatemia

Psychiatric Disorders

Not known

• Lethargy
• Mood disturbances

Nervous System Disorders

Very common

• Headache

Common

• Dizziness

Not known

• Migraine
• Confusion
• Hypertonia

Eye Disorders

Not known

• Visual disturbances
• Eye pain
• Conjunctivitis

Ear and Labyrinth Disorders

Not known

• Tinnitus

Cardiac Disorders

Common

• Lower limb oedema
• Palpitations
• Hypotension
• Tachycardia

Not known

• Atrioventricular block
• Angina pectoris
• ST segment depression
• Inverted T wave

Vascular Disorders

Common

• Orthostatic hypotension

Not known

• Deep-vein thrombophlebitis
• Excessive fall in blood pressure which leads to cerebral or myocardial ischaemia or transient blindness

Respiratory, Thoracic and Mediastinal Disorders

Not known

• Pulmonary oedema cases have been also reported when used as tocolytic during pregnancy)
• Respiratory disorder

Gastrointestinal Disorders

Common

• Nausea and vomiting

Not known

• Paralytic ileus
• Constipation
• Dyspepsia

Hepato-biliary Disorders

Not known

• Hepatic enzyme increased (liver function abnormalities)

Skin and Subcutaneous Tissue Disorders

Common

• Flushing

Not known

• Erythema
• Gingival hyperplasia
• Rash
• Pruritus

Musculoskeletal, Connective Tissue and Bone Disorders

Not known

• Myalgia
• Tremor

Renal and Urinary Disorders

Not known

• Micturition disorders including increased frequency

Reproductive System and Breast Disorders

Not known

• Gynecomastia
• Impotence

General Disorders and Administrative Site Conditions

Not known

• Phlebitis
• Fever

• Beta-blockers
• Dantrolene
• Magnesium
• CYP3A4 inducers
• Carbamazepine
• Phenobarbital
• Phenytoin
• Fosphenytoin
• Primidone
• Rifampicin
• CYP3A4 inhibitors
• Cimetidine
• Itraconazole
• Grapefruit juice
• Cyclosporine
• Tacrolimus
• Sirolimus
• Digoxin
• Medications which could potentiate the antihypertensive effect
• Baclofen
• Alpha-blockers
• Tricyclic antidepressants
• Neuroleptics
• Opioids
• Amifostine
• Intravenous corticosteroids
• Tetracosactide
• Inhalational anaesthetics
• Competitive neuromuscular blockers

• Blood pressure
• Heart rate

Incompatibilities and special handling

• In the absence of compatibility studies, this medicine must not be mixed with other medicines except those mentioned under dose recommendations or the product information
• The ampoules must be kept in the outer carton in order to protect them from light. Not for use undiluted
• The shelf life before opening is 24 months; After opening: The physicochemical stability of the undiluted solution or diluted in a solution of 5% dextrose in water in a polypropylene syringe has been demonstrated for 24 hours at temperatures of + 25°C, away from light. Nonetheless, from a microbiological standpoint, the product should be used immediately
• Any unused product or waste material should be disposed of in accordance with local requirements

Nicardipine is a second-generation slow calcium channel inhibitor, and belongs to the phenyl-dihydropyridine group. Nicardipine has greater selectivity for L-type calcium channels in vascular smooth muscle than cardiac myocytes. At very low concentrations it inhibits the influx of calcium into the cell. Its action is produced mainly on arterial smooth muscle. This is reflected in relatively large and rapid changes in blood pressure, with minimal inotropic changes in cardiac function (baroreflex effect). Nicardipine is a potent vasodilator which diminishes total peripheral resistance and lowers blood pressure. Heart rate is temporarily increased, because of a decrease in after-load, cardiac output is markedly and durably increased. Vasodilator action occurs in both acute dose administration and chronic administration in the large and small arteries, increasing blood flow and improving arterial compliance. Renal vascular resistance is decreased.

Injection 10mg/10ml

• Nicardipine Equity (Equity Pharmaceuticals)