P&T News: September 2000

Safety Concerns Associated with the Use of Immediate-Release Sublingual Nifedipine

Barbara A. Mutnick, R.Ph., M.H.P., Clinical Pharmacist, Department of Pharmaceutical Care
Peer Review Status: Internally Peer Reviewed by William G. Haynes, M.D., Associate Professor and Head, Division of Clinical Pharmacology, Department of Internal Medicine

This past January the Institute for Safe Medication Practices (ISMP), a national watchdog organization that documents adverse drug events and educates healthcare providers about ways to avoid recurrences, distributed a safety brief advising against the continued use of sublingual nifedipine for treatment of hypertensive crises. The groundwork for this recommendation was laid in 1985 when the Cardiorenal Advisory Committee of the Food and Drug Administration determined that sublingual nifedipine should not be approved for the treatment of hypertensive crises.1,2 A hypertensive emergency, one category of crises, is defined as a situation that requires immediate blood pressure reduction, though not necessarily to normal range, in order to prevent target organ damage. Hypertensive emergencies include: hypertensive encephalopathy, intracranial hemorrhage, unstable angina pectoris, acute myocardial infarction, acute ventricular failure with pulmonary edema, dissecting aortic aneurysm, and eclampsia. Hypertensive urgencies are situations where it is desirable to reduce blood pressure in a few hours and include: upper levels of stage 3 hypertension, hypertension with optic disc edema, progressive target organ complications, and severe perioperative hypertension.3 Elevated blood pressure alone, in the absence of symptoms or new or progressive target organ damage, rarely requires emergency therapy.

Until recently, sublingual nifedipine was routinely used for that indication. It was not uncommon to find this therapy as a standing order used in emergency rooms, nursing homes, and hospital units. Sublingual nifedipine use became popular because unlike intravenous agents used to treat hypertensive crises (e.g., sodium nitroprusside, nitroglycerin, diazoxide, and others), the sublingual route could be employed by placing a perforated capsule under the tongue, squeezing the liquid drug out of the capsule and directing it under the tongue, or by directing a patient to bite the capsule before swallowing it. Also, it was generally believed that patients did not need to be closely monitored since decreases in blood pressure were supposed to be proportional to pretreatment levels and hypotension was said to be rare.

However, the use of sublingual nifedipine became questionable for a number of reasons. It became apparent from a number of studies4-6 that the administration of sublingual nifedipine results in slowly absorbed drug and low plasma levels. Patients who bit the capsule and then swallowed had higher plasma blood levels that were attained more quickly than those attained by only the sublingual route.4 Other studies confirmed that nifedipine is poorly absorbed after buccal administration and that this method delayed attaining peak plasma concentration.5,6 It would appear that the antihypertensive effects of sublingual nifedipine are due to the intestinal absorption of the drug that may have taken place.

Despite the purported safety of sublingual nifedipine, there have been case reports of serious adverse effects secondary to its use. The authors of an article in JAMA in 1996 reviewed the literature for the use of nifedipine for these types of crises and uncovered a number of serious, and in some cases fatal, adverse effects. These authors discovered cases of neurologic or cardiac effects, combinations of both neurologic and cardiac effects in the same patient, and in one case, fetal distress when the drug was administered to a woman who was pregnant. The neurologic effects ranged from dizziness, aphasia, hemiparesis, loss of consciousness, and stupor. Cardiac effects of administration of the drug included: ECG changes (inverted T-wave, ST-segment depression), syncope, heart block, palpitations, myocardial infarction (in five patients), and sinus arrest. The abrupt decrease in arterial pressure in hypertensive emergencies occurs through the following mechanisms: 1) the actual uncontrollable fall in BP; 2) the peripheral vasodilation which produces a steal phenomenon in various vascular beds; and 3) the reflex cardioacceleration and increased catecholamine release.7 Of the sixteen cases presented in the article, two deaths were reported and the outcome for two additional patients was unknown.

The nifedipine safety alert published in ISMP's biweekly newsletter was prompted by an October 1999 editorial1 which took the opportunity to stress the danger of this practice. The editorial also pointed out the change in "The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC-VI) recommendations versus JNC-V.3 The 1997 JNC-VI report advised that immediate acting nifedipine for treatment of hypertensive emergencies is "unacceptable" because of the inability to control the rate or degree of fall in blood pressure.

Recommendations
The JNC-VI report included a table of alternate intravenous drugs to use in hypertensive emergencies. (Table 1 provides information on the agents currently stocked at UIHC.) The initial goal is to reduce blood pressure by no more than 25% (within minutes to two hours), then toward 160/100 mm Hg within 2 to 6 hours, avoiding excessive falls in blood pressure that may precipitate renal, cerebral, or coronary ischemia.

Treatment of hypertensive urgencies can usually be managed with oral therapy8 (Table 2). For elevated blood pressure without symptoms, oral therapy should be initiated only after all attempts to remove the causes of elevation of blood pressure, such as pain or distention of the urinary bladder, have been accomplished. Blood pressure should be monitored at 15 to 30 minute intervals; if it persists at greater than 180/120 mm Hg, then an oral therapy described below should be initiated.

Captopril
Captopril is a fast-acting ACE inhibitor that can be administered sublingually. Abrupt and first dose hypotension is rarely seen with the administration of ACE inhibitors. The rare cases are usually observed in patients with high renin levels. This drug should be used cautiously in patients with significant renal insufficiency or who are volume depleted.

Clonidine
Clonidine is a centrally acting agonist, with a relatively slow onset of action that can be administered hourly to safely reduce elevated blood pressure. Sedation is a major side effect of the drug. It also can cause rebound hypertension upon sudden discontinuation, so it should not be used in patients in whom compliance may be an issue.

Labetalol
This agent is an alpha and beta blocker that can be administered hourly. It also has a slower onset of action.

Table 1. Parenteral Drugs for Treatment of Hypertensive Emergencies

Drug

Onset

Special Indications

Sodium nitroprusside
(Nitropress®, Nipride®)

Immediate

Most hypertensive emergencies; caution with high intracranial pressure or azotemia

Nitroglycerin
(Nitrostat®)

2-5 minutes

Coronary ischemia

Enalaprilat
(Vasotec®)

15-30 minutes

Acute left ventricular failure; avoid in acute myocardial infarction

Hydralazine
(Apresoline®)

IV: 10-20 minutes
IM: 20-30 minutes

Eclampsia

Labetalol
(Normodyne®, Trandate®)

5-10 minutes

Most hypertensive emergencies except acute heart failure

Esmolol
(Brevibloc®)

1-2 minutes

Aortic dissection; perioperative

(Phentolamine
(Regitine®)

1-2 minutes

Catecholamine excess

Adapted from: JVN-VI: Arch Intern Med 1997;157:2413-46.

Table 2. Oral Agents for Treatment of Hypertensive Urgencies

Drug

Class

Dose

Onset

Duration

Captopril
(Capoten®)

ACE inhibitor

6.5 to 50 mg

15 minutes

3-5 hours

Clonidine
(Catapres®)

Central alpha agonist

0.2 mg initially, then 0.1 mg/hour; up to 0.8 mg

0.5-2 hours

6-8 hours

Labetalol
(Normodyne®, Trandate®)

Alpha and beta blocker

100-200 mg

0.5 to 2 hours

8-12 hours

Adapted from: Kaplan NM. Clinical Hypertension. 7th ed. Baltimore: Williams & Wilkins; 1998.

Summary
The sublingual administration of immediate-release nifedipine has been demonstrated to not only result in unreliable absorption of the drug, but also has been shown to precipitate serious, and in some cases, fatal adverse effects. Other oral agents have been shown to be safe and effective methods to lower blood pressure when used to treat cases of hypertensive urgency.

References

1. Arch Intern Med 1999;159:2259-60.

2. The Lancet 1991;338:881.

3. Arch Intern Med 1997;157:2413-46.

4. The Lancet 1987;2:1363-5.

5. Angiology 1992;43:477-81.

6. Am J Med 1986;81(suppl 6A):2-5.

7. JAMA 1996;276:1328-31.

8. Clinical Hypertension 7th ed. Baltimore:Williams & Wilkins;1998:276-7.

PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS

STRENGTHS ADDED TO STOCK

LAMIVUDINE
A 100 mg tablet (Epivir-HBV®) has been added to stock.

RIFAMPIN
A 150 mg capsule has been added to stock.

________________________

DRUGS DELETED FROM STOCK

CISAPRIDE TABLETS AND ORAL SUSPENSION
Withdrawn from the U.S. market due to safety concerns. Metoclopramide, lansoprazole, and cimetidine are available.

FACTOR IX INJECTION - PROPLEX-T®
Deleted due to low use. Fieba-VH® and NovoSeven® are available.

PLAGUE VACCINE
Discontinued by the manufacturer.

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