Amlodipine Side Effects: Withdrawal and Discontinuation Syndrome Explained

Does amlodipine have a withdrawal syndrome?

A withdrawal, or discontinuation, syndrome is a recognizable cluster of symptoms that follows removal of a drug, such as the problems noted with abrupt beta-blocker cessation [3]. Investigators have looked for one with amlodipine in two studies: a 3-day interruption in people whose hypertension was controlled, where blood pressure did not rise significantly compared with continued treatment, and a randomized withdrawal phase in stable angina, where the authors reported no significant problems of the beta-blocker type [2][3]. Both were short: 3 days off drug in one, a 4-week withdrawal phase in the other [2][3].

The Norvasc label's warnings and precautions cover three things: symptomatic hypotension, particularly in severe aortic stenosis; worsening angina or acute myocardial infarction after starting or increasing the dose, particularly in severe obstructive coronary artery disease; and slow titration in severe hepatic impairment, where the half-life reaches 56 hours [1]. None of these is a discontinuation reaction.

Amlodipine is a dihydropyridine calcium channel blocker and a peripheral arterial vasodilator that lowers blood pressure by reducing peripheral vascular resistance [1]. Its binding to the calcium channel receptor has a gradual rate of association and dissociation, so the onset of effect is gradual [1]. The terminal half-life is about 30 to 50 hours, and steady state is reached after 7 to 8 days of once-daily dosing [1].

What happens to blood pressure when amlodipine is stopped

MedlinePlus describes amlodipine as controlling high blood pressure rather than curing it [4]. With a half-life of about 30 to 50 hours, drug concentrations fall over days after the last tablet [1].

The direct test of a short interruption came from Biston and colleagues in 1999. Patients with mild to moderate hypertension controlled by amlodipine 5 mg once daily for 6 weeks were randomized either to continue 5 mg or to take amlodipine for 12 more days followed by 3 days of placebo. After this double-blind phase, the placebo group showed no significant increase in blood pressure compared with the continued-treatment group, by either office or ambulatory monitoring [2].

The limits are the design: a 3-day gap in people already controlled on 5 mg, so the study says nothing about a longer interruption, a higher dose or uncontrolled hypertension [2].

For a single missed dose, MedlinePlus says to take it when remembered, to skip it if the next scheduled dose is less than 12 hours away, and not to double up [4].

Angina after stopping amlodipine

MedlinePlus says amlodipine does not stop chest pain once it starts, and that a different medicine may be prescribed for chest pain that is already underway [4].

Mehta and Lopez studied withdrawal in angina in 1994. Amlodipine monotherapy, 5 to 10 mg once daily, was given to 226 patients with chronic stable angina for 8 weeks; responders, meaning those with at least a 7% improvement in exercise time, then entered a randomized, placebo-controlled, double-blind withdrawal phase lasting 4 weeks [3]. The absence of a beta-blocker-type withdrawal signal comes from that phase, so it applies to responders with stable angina [3].

The label's angina warning concerns starting or increasing the dose: worsening angina and acute myocardial infarction can develop after starting or increasing amlodipine, particularly in severe obstructive coronary artery disease [1].

Symptoms around a dose change

Palpitations are a known amlodipine effect during treatment, and they are dose related: 0.7% at 2.5 mg, 1.4% at 5 mg and 4.5% at 10 mg, versus 0.6% on placebo [1]. Dizziness follows a similar pattern: 1.1%, 3.4% and 3.4% versus 1.5% [1].

Timing alone cannot show whether a new symptom is caused by stopping amlodipine. MedlinePlus lists more frequent or severe chest pain, a rapid, pounding or irregular heartbeat, and fainting as serious side effects that need immediate medical attention [4].

Does amlodipine need to be tapered?

The label's dosing section describes how to start and increase amlodipine: 5 mg once daily for most adults, 10 mg maximum, with 7 to 14 days between titration steps unless faster titration is clinically warranted, and 2.5 mg starting doses for small, fragile or elderly patients, for people with hepatic impairment, and when adding amlodipine to other antihypertensives [1]. It describes no tapering schedule for stopping [1].