DI Request Form

Date: 08/02/2021
Time: 10:00 AM
Requester: Pharmacist

Classification (highlight)

Tablet/Product ID Natural products Toxicology

Product Availability Pharmacotherapy Pregnancy/lactation
Product Information ADR Compounding
Drug Administration Drug Interaction Pharmacokinetics
Foreign Product ID Stability/compatibility Literature Search

Background Information:

1. How old is the patient?

2. What allergies does the patient have?
3. Patient PMH?
4. What is the indication the medication is being used for?
5. What are the current medications the patient is taking?
6. How long will the patient be using this therapy for?
7. What specific CCB are you inquiring about?
8. Does the patient have a history of being on CCB?

Question: What is the incidence of gingival hyperplasia within the calcium channel blocker class?

HC professional
Search Strategy

Source Search string Limits # of results Relevant citations and comments

MM Amlodipine 1  The incidence of gingival hyperplasia induced by
calcium channel antagonists is unknown but may
be as high as 10% of nifedipine users. There are
currently several proposed mechanisms of action
for this adverse effect. These include inflammation
from bacterial plaque and increased sulfated
glycosaminoglycans, immunoglobulins and folic
acid, or perhaps a local toxic effect from the
extremely high concentrations of some agents
found in the gingival crevicular fluid.
MM Drug-consult: Calcium Channel Antagonist- 1  The most common adverse effect of calcium channel
Induced Gingival Hyperplasia blockers is drug-induced gingival hyperplasia; gingival
overgrowth, though, seems to occur more frequently
than overt hyperplasia. Although nifedipine has
caused the most cases of gingival hyperplasia, similar
adverse effects have been observed when using
other calcium channel blockers.
 A single-blind, case-controlled study of 115 geriatric
males found that nifedipine was associated with 38%
of gingival hyperplasia, diltiazem with 21%, and
verapamil with 19%. In adult and pediatric renal
transplant patients exposed to nifedipine as well as
other agents potentially contributing, an overall
gingival hyperplasia incidence of 44% in adults and
27% in children was noted.
 Histocompatibility antigens class I and II may
contribute to gingival hyperplasia as well.
PubMed gingival hyperplasia AND calcium channel 160 DOI: 10.1111/j.1600-051X.2010.01574.x
blockers
Within the study population, 103 cases of gingival hyperplasia
were identified and matched to 7677 controls. The risk of
gingival hyperplasia was higher in current users of CCBs
especially in dihydropyridines and benzothiazepine
derivatives than in RAS drug users. The risk increased in
patients using more than the recommended daily dose (and
when the duration of current use was <1 month.

CCB users are twofold more likely to develop gingival

hyperplasia than those taking RAS drugs. Dihydropyridines
and benzothiazepine derivates showed the strongest
association, which was dose dependent.

DOI: doi.org/10.1016/j.jebdp.2011.03.009

Current use of CCBs (compared with no use of CCBs

regardless of RAS use) doubled the risk of gingival
hyperplasia. No association between past use of CCBs and
gingival hyperplasia was observed. The current use of
nifedipine, diltiazem, dihydropyridine, and benzothiazepine
derivatives was associated with an increased risk of gingival
hyperplasia compared with no use of CCBs or anytime use
of RAS drugs. A significant dose response was observed in
current users of CCBs. This risk doubled for doses equal to
1 defined daily dose (DDD) equivalent and tripled for daily
dosages above 1 DDD. Confounding by severity of
hypertension and other known risk factors for gingival
hyperplasia was not observed.

DOI: 10.1902/jop.1999.70.1.63
More than six percent (6.3%) of subjects taking nifedipine
were seen to have significant overgrowth. This overgrowth
was statistically greater than the amount of overgrowth
seen in either of the other 2 drug groups or the control
population. The prevalence of gingival overgrowth induced
by amlodipine or diltiazem was not statistically significant
when compared to the control group. The severity of
 overgrowth within the nifedipine group was found to be
related to the amount of gingival inflammation and to the
gender of the subject, with males being 3 times as likely to
develop overgrowth than females.

The prevalence of clinically significant overgrowth related

to chronic medication with calcium channel blockers is low,
i.e., 6.3% for nifedipine. Males are 3 times as likely as
females to develop clinically significant overgrowth. The
presence of gingival inflammation is an important cofactor
for the expression of this effect.

DOI: 10.1902/jop.1992.63.5.453

The records of 5,000 dental patients were reviewed for

history of verapamil use between 1987 and 1990. Twenty-
four dentate patients who received verapamil for more
than 1 year were identified. Of these, gingival hyperplasia
occurred in 1 patient (4.1%) that was limited to the
mandibular attached gingiva. Onset of gingival overgrowth
was associated with drug dosage, bacterial accumulation,
and gingival inflammation. Histologically, the findings
resembled that seen in hyperplasia induced by phenytoin,
cyclosporin, and other calcium channel blockers. Our data
suggest that gingival hyperplasia caused by verapamil
occurs less frequently than nifedipine-induced gingival
hyperplasia.
Facts and Calcium channel blockers Nifedipine incidence: < 10%
Comparisons Verapamil incidence: < 19%

No incidence reports for other CCBs.

Meyler’s Calcium Channel Blocker Gingival Gingival hyperplasia, similar to that seen with phenytoin
hyperplasia and ciclosporin, is a rare but well-recognized adverse effect
of nifedipine. It has also been reported in patients taking
felodipine, nitrendipine, and verapamil, suggesting that
this adverse effect is a class effect. Only one case of
gingival hyperplasia related to calcium channel blockers
was reported to the Norwegian Adverse Drug Reaction
Committee up to 1991, despite their widespread use.
However, subclinical gingival hyperplasia on tissue
histology was found in 83% and 74% of patients taking
nifedipine and diltiazem respectively. The reaction
generally occurs within a few months of starting
treatment, and in some cases drug withdrawal produces
marked regression of clinical hyperplasia. The mechanism
of this adverse effect is unclear but has been proposed to
involve a hormonal imbalance in the hypothalamic–
pituitary–adrenal axis.

Periodontal disease has been assessed in 911 patients

taking calcium channel blockers, of whom 442 were taking
nifedipine, 181 amlodipine, and 186 diltiazem, and in 102
control subjects. There was significant gingival overgrowth
in 6.3% of the subjects taking nifedipine, while the
prevalence induced by amlodipine or diltiazem was not
significantly different than in the controls. The severity of
overgrowth in the nifedipine group was related to the
amount of gingival inflammation and to sex, men being
three times as likely to develop overgrowth than women.
Response:
During my research for this question, I found that it is well documented that gingival hyperplasia is a common adverse effect associated with
calcium channel blockers, though certain CCBs are associated with a high incidence. There was similar data in tertiary databases (Micromedex
and Facts and Comparisons), with gingival hyperplasia listed as an adverse effect, though the incidence rates differed among calcium channel
blockers. Micromedex reported that nifedipine was the most reported cause of gingival hyperplasia, although similar effects were observed
with the use of other calcium channel blockers. A case-control study of 115 geriatric males found that nifedipine was associated with 38% of
gingival hyperplasia, diltiazem with 21%, and verapamil with 19%. Moreover, nifedipine and other agents potentially contributing to gingival
hyperplasia caused an overall incidence of 44% in adult patients and 27% in pediatric patients in renal transplant patients. According to a
retrospective study focusing on periodontal disease, 6.3% of the 442 patients taking nifedipine developed significant gingival overgrowth.
There was a significant relation between gingival inflammation and the severity of gingival overgrowth in the nifedipine group, with men having a
three-fold higher chance of developing overgrowth than women. Another study, comparing CCBs to RAS agents, found that dihydropyridines and
benzothiazepine derivatives showed the strongest association, which was dose dependent.