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Case Report

Case report on low dose of

Cilnidipine: A fourth‑generation
calcium channel blocker‑induced
gingival overgrowth
Sameera Gopinath, Vadakkedath Venugopal Harishkumar,
Vediyera Chandroth Santhosh, Sreekanth Puthalath

Department of Abstract:
Periodontics, KMCT Drug‑induced gingival overgrowth is a frequently observed adverse effect of antihypertensive drug calcium
Dental College, channel blockers (CCBs). Gingival enlargements are more common with the dihydropyridine class of CCBs. The
Kozhikode, Kerala, India fourth‑generation dihydropyridine CCB Cilnidipine was introduced in 1995 and is used as an antihypertensive
agent for patients in the Indian subcontinent. This is the first report in literature to document an isolated case of
generalized gingival overgrowth induced by the long‑term use of low dose of cilnidipine in an elderly female
patient who is under antihypertensive therapy. Gingival overgrowth is an adverse drug reaction of new‑generation
CCB Cilnidipine when administered even as low‑dose antihypertensive therapy agent. Physicians and dentists
should identify such late changes in susceptible individuals.
Key words:
Adverse drug reaction, calcium channel blocker, cilnidipine, dihydropyridine, gingival overgrowth
Access this article online
Website:
www.jisponline.com INTRODUCTION CASE REPORT
DOI:

D
10.4103/jisp.jisp_557_18 rug‑induced gingival overgrowth (DIGO)
Quick Response Code: is an adverse effect of anticonvulsants,
immunosuppressants, and calcium channel
blockers (CCBs).[1,2] CCBs are a class of widely used
antihypertensive agents. DIGO is more common
with the dihydropyridine class of CCB. The
first‑ and second‑generation dihydropyridines
(nifedipine, verapamil, diltiazem, and
amlodipine) are associated with DIGO.[3,4] The
prevalence of nifedipine‑induced gingival
overgrowth ranges from 20% to 83%, while for
other CCBs such as diltiazem, amlodipine, and
verapamil, the prevalence is around 74%, 3.3%,
and 21%, respectively.[3,4]
The fourth‑generation dihydropyridine CCBs are
now in common use as antihypertensive agents.
Cilnidipine is a promising fourth‑generation CCB
Address for
that came into market in 1995 and is widely used as
correspondence: an antihypertensive agent in India. So far, only one
case of fourth‑generation dihydropyridine‑induced
Dr. Sameera G. Nath,
20/1312, “Krishneeyam”, gingival overgrowth has been reported in
Thiruvannur Road, literature.[4] It was a report of a Japanese patient
Panniyankara, Kallai Post,
who had a combination therapy of Cyclosporin
Kozhikode ‑ 673 003, A and Cilnidipine. Interestingly, DIGO is a
Kerala, India.
known adverse effect of the immunosuppressant
E‑mail: sameeradr@
rediffmail.com Cyclosporin A.[1] Our case report could be the
first report in literature to document the gingival
Submission: 29‑08‑2018 overgrowth as an adverse effect of the long‑term
Accepted: 20‑01‑2019 use of low‑dose Cilnidipine alone.
© 2019 Indian Society of Periodontology | Published by Wolters Kluwer - Medknow 377
A 55‑year‑old female patient, taking once‑daily
dosage of Cilnidipine – 5 mg, was referred
by her physician to the Periodontics division
of our Dental College, for improving her
oral hygiene [Figure 1a‑c]. She was under
antihypertensive treatment for 6 years. She gave
a history of slowly progressing enlargements on
her gums for 1 year. She also reported discomfort
while brushing the teeth due to bleeding from
gums in the last 6 months after which the size of
the swelling enlarged rapidly.
Intraorally, the gingiva was enlarged in relation
to maxillary and mandibular teeth, and it was
firm, diffuse, and lobulated and characteristically
appears to project from beneath the gingival
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How to cite this article: Gopinath S, Harishkumar VV,
Santhosh VC, Puthalath S. Case report on low dose
of Cilnidipine: A fourth-generation calcium channel
blocker-induced gingival overgrowth. J Indian Soc
Periodontol 2019;23:377-80.
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Gopinath, et al.: Cilnidipine‑induced gingival overgrowth
a b
c
Figure 1: (a) Frontal view of the patient demonstrating the drug‑induced gingival
enlargement, complicated by secondary inflammatory changes; (b) left lateral view;
(c) right lateral view
margin, with Grade II to Grade III gingival overgrowth according
to Buchner et  al.’s grading criteria. In the maxillary arch, the
overgrowth extended labially from 22 to 27; it was localized
around 12. In the mandibular arch, the overgrowth extended
labially from the distal aspect of 33–43 regions and localized
around 46. There was minimal involvement of the palatal or
lingual areas. Few areas showed signs of secondary inflammatory
changes. Teeth in the involved area had plaque and calculus.
The Oral Hygiene Index score was 2 (fair oral hygiene). The
presence of the enlargement made plaque control difficult,
resulting in secondary inflammatory changes especially in the
mandibular teeth, which complicated the gingival overgrowth
caused by the drug. Since she was undergoing antihypertensive
therapy and no other known drugs which could induce gingival
overgrowth were prescribed, the case was clinically diagnosed as
drug‑induced (Cilnidipine) gingival overgrowth with secondary
inflammatory changes which was confirmed histologically.
Histologically, there was pronounced hyperplasia of the
connective tissue and epithelium. There was acanthosis of
the epithelium and elongated rete pegs were extending into
the connective tissue, along with densely arranged collagen
bundles, many fibroblasts and new blood vessels, and few
inflammatory cell infiltrates [Figure 2].
Clinical management
She was advised to undergo a full‑mouth periodontal
rehabilitation along with drug modification after consulting
her physician. Unfortunately, 1 week later, we lost the patient
as she succumbed to massive cardiac arrest. A limitation of
this case report is that radiographs could not be obtained, and
importantly, we could not deliver dental treatment for her.
DISCUSSION
DIGO is an adverse effect of anticonvulsants,
immunosuppressants, and CCBs[1,2] with some common clinical
characteristics such as genetic predisposition, more prevalent
in anterior gingiva, younger individuals, and onset within
3 months of use.[5‑8]
CCBs are drugs that were developed for the treatment of
various cardiovascular conditions. These drugs are the
378 Journal of Indian Society of Periodontology - Volume 23, Issue 4, July-August 2019
Figure 2: Histopathologic view
dihydropyridine derivatives, the benzothiazine derivatives,
and the phenylalkylamine derivatives. The first‑ and
second‑generation dihydropyridines (e.g., nifedipine,
verapamil, diltiazem, and amlodipine) are associated with
DIGO.[3,4] CCBs inhibit the intracellular Ca2+ uptake and
stimulate the gingival fibroblasts. There exists a functional
heterogenicity in the gingival fibroblasts in response to various
stimuli.[1] Only susceptible patients receiving the same drug
develop DIGO. Individuals with DIGO may have fibroblasts
with an abnormal susceptibility or fibrogenic response to the
drug.
Several factors may be involved in the pathophysiology
of CCB‑induced gingival overgrowth. Age and genetic
predisposition of the host, alteration in gingival connective
tissue homeostasis, pharmacokinetic variables, inflammatory
changes, and drug action on growth factors are few of the factors.
The pathogenesis of DIGO involves both noninflammatory
and inflammatory pathways. The noninflammatory pathway
includes (1) defective collagenase activity which could be due
to decreased uptake of folic acid, (2) the blockage of aldosterone
synthesis in the adrenal cortex and consequent feedback increase
in adrenocorticotropic hormone level, and (3) upregulation of
keratinocyte growth factor. Inflammation may develop as a
result of (1) the direct toxic effects of the concentrated drug
in the crevicular gingival fluid and/or (2) bacterial plaques
which upregulate several pro‑inflammatory cytokines such
as transforming growth factor‑β1, interleukin 1 (IL‑1) β, and
IL‑6.[1] Many studies have shown an association between the
oral hygiene status and severity of DIGO.[1,2] In the present case,
the poor plaque control had worsened the existing gingival
enlargement and therefore further complicated the oral hygiene
maintenance.
Many reports have shown that Amlodipine 10 mg/day
caused DIGO within the first 6 months of use.[1‑3] Interestingly,
there are only few reports on DIGO induced by short‑term
administration of low‑dose Amlodipine (5 mg).[9] For the
first time in literature, this is a case report on Cilnidipine
alone‑induced gingival enlargement. In contrast to the
available knowledge on CCB‑induced gingival overgrowths,
our case is unique since it highlights (1) a fourth‑generation
CCB cilnidipine‑induced gingival enlargement, (2) low‑dose
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Gopinath, et al.: Cilnidipine‑induced gingival overgrowth

Table 1: Calculation of adverse drug reaction for Cilnidipine based on Naranjo adverse drug reaction probability scale
Question Yes No Don’t know Score
Are there previous conclusive reports on this reaction? +1 0 0 0
Did the adverse event appear after the suspected drug was administered? +2 −1 0 +2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 0
Did the adverse event reappear when the drug was readministered? +2 −1 0 0
Are there alternative causes (other than the drug) that could on their own have caused the reaction? −1 +2 0 +2
Did the reaction reappear when a placebo was given? −1 +1 0 0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic? +1 0 0 0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +1 0 0 0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 0
Was the adverse event confirmed by any objective evidence? +1 0 0 +1
Total score >9 ‑ Definite ADR; 5‑8 ‑ Probable ADR; 1‑4 ‑ Possible ADR; 0 ‑ Doubtful ADR. ADR–Adverse drug reaction

Table 2: The World Health Organization-Uppsala Monitoring Centre causality assessment scale
Causality term Assessment criteria (all points should be reasonably complied)
Certain • Event or laboratory test abnormality; with plausible time relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible(pharmacologically, pathologically)
• Event definitely pharmacologically or phenomenologically (ie; an objective and specific medical disorder or a
recognized pharmacological phenomenon)
• Rechallenge satisfactory; if necessary
Probable /Likely • Event or laboratory test abnormality; with reasonable time relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible • Event or laboratory test abnormality; with reasonable time relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality; with a time to drug intake that makes a relationship improbable (but not
impossible)
• Disease or other drugs provide plausible explanation
Conditional/ Unclassified • Event or laboratory test abnormality
• More data for proper assessment needed , or
• Additional data under examination
Unassessable /Unclassified • Report suggesting an adverse reaction
• Cannot be judged because information is insufficient or contradictory
• Data cannot be supplemented or verified
Adapted from Syed AZ. Adverse drug reactions and causality assessment scales - Letter to the Editor. Lung India 2011;28:152-3.

drug‑induced changes, and (3) long‑term adverse effect of
the drug. The structural similarity of cilnidipine with other
dihydropyridines can be hypothesized to be the probable
reason for this adverse drug reaction (ADR).
The ADR Probability Scale often referred to as the Naranjo
Scale is a method to assess whether there is a causal
relationship between an identified untoward clinical
event and a drug using a simple questionnaire to assign
probability scores. [10] This scale was developed to help
standardize assessment of causality for all ADRs except
drug‑induced liver injury [Table 1]. According to this ADR
scale, a “probable” causal relationship with Cilnidipine
was assessed by Naranjo score (score = 4). Furthermore, a
“possible” causal relationship is assessed using the World
Health Organization‑Uppsala Monitoring Centre scale for
causality assessment [Table 2].[11] More cases of DIGO caused
by Cilnidipine need to be diagnosed and assessed after
treatment to confirm the causal relationship.
To summarize, gingival overgrowth is an ADR of
new‑generation CCB Cilnidipine when administered even
as low dose (5 mg). Physicians and dentists should identify
such late changes in susceptible individuals. Interdisciplinary
approaches in them need to be focused on terminating or
modifying the offending drug along with effective oral hygiene
maintenance measures.
CONCLUSION
For the first time in the literature on DIGO case reports, this is a
case report of cilnidipine‑alone‑induced gingival enlargement
with some unique characteristics: (1) A fourth‑generation
CCB cilnidipine‑alone‑induced gingival hyperplasia,
(2)  low‑dose‑induced changes, and (3) long‑term adverse effect
of this antihypertensive drug. Interdisciplinary approaches
focused on terminating or modifying the offending drug along
with effective oral hygiene maintenance measures.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and
other clinical information to be reported in the journal. The
patients understand that their names and initials will not be
published and due efforts will be made to conceal their identity,
but anonymity cannot be guaranteed.

Journal of Indian Society of Periodontology - Volume 23, Issue 4, July-August 2019 379
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Gopinath, et al.: Cilnidipine‑induced gingival overgrowth

Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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