Observational Prospective Cohort Study to Evaluate the Incidence of Adverse Events (AE), Risk Factors, and Drug Utilization Patterns Related to Treatment With BUSCAPINA COMPOSITUM N From March to December 2016 in Patients From Metropolitan Lima
Conditions: Acute Pain, Dysmenorrhea
Sponsor: Boehringer Ingelheim

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MINIMUM CRITERIA TO BE CONSIDERED FOR THE PRESENTATION OF THE ACTIVE PHARMACOVIGILANCE PLAN
ACTIVE PHARMACOVIGILANCE
REGISTER OF THE POSTMARKETING STUDY 
NCT number:
Date of protocol 
submission: 
1. ORGANIZATION / REQUIRING INSTITUTION
Name of the 
Organization/ 
Institution:
Boehringer Ingelheim Perú S.A.C
Type of 
Organization 
/ Institution:
Pharmaceutical Industry
Legal address:
Av. Canaval y Moreyra 480 
Urb. Limatambo (piso 20)
District:
San Isidro
Province:
LIMA
Region:
Lima
Tax Number:
e-mail:
Phone:
2. INFORMATION ABOUT THE PHRAMACEUTICAL PRODUCT
Tradename of the pharmaceutical product 
Generic name 
Type of 
product
ATC
BUSCAPINA COMPOSITUM N
Hioscina N – Butilbromuro /
Paracetamol
Chemical 
synthesis
A03DB04
Number of sanitary 
register 
E8613
Date of 
sanitary 
register 
Expiration date: 7/7/2020
Safety problems 
identified 
Hepatobiliary disorders: Increased hepatic transaminases (ASAT/ALAT).
Observational study 
proposed (analytic or 
descriptive) 
Descriptive cohort study
3. GENERAL INFORMATION OF THE PHASE IV STUDY
Study Title (average 20 words) 
Observational prospective cohort study to evaluate the incidence of adverse events (AE), risk factors, and
drug utilization patterns related to treatment with BUSCAPINA COMPOSITUM N from March to December
2016 in patients from Metropolitan Lima.
Study rationale or problem identified:
Buscapina Compositum N is an oral analgesic indicated for adults and children over 12 years old, for the relief of 
spasmodic pain in stomach and intestinal illness, colic-type pain and functional disorders of biliary and urinary 
tracts and of the female genital organs. Each tablet of Buscapina Compositum N has a combination of 10 mg of 
hyoscine n-butylbromide and 500 mg of Paracetamol. The dose of Buscapina Compositum N is one to two tablets 
by mouth every 8 hours, swallowed whole with sufficient water. The following is a description of each of the 
components of Buscapina Compositum N, as well as the studies of efficacy and safety that have evaluated these 
components. 
Paracetamol
Paracetamol is a derivative of acetanilide with antipyretic and analgesic properties, and weak anti-inflammatory 
properties. The mechanism of action of paracetamol is still debated. The mechanism proposed was the inhibition of 
prostaglandin synthesis by blocking cyclooxygenase (COX) enzymes COX-1, COX-2 and a variant of COX-1 
centrally expressed, COX-3. But to explain the differences with other analgesics, other mechanisms were 
postulated for paracetamol: central activation of descending serotoninergic pathways, inhibition of the nitric oxide 
synthase enzyme, involvement of the metabolite N-arachidonoylphenolamine (AM404) which activates the vanilloid 
NCT02910167
10 January 2017

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subtype 1 receptor (TRPV1), influence on subtype 1 cannabinoid receptors (CB1) and inhibition of the uptake of the 
endocannabinoid anandamide. Endogenous opioids could also contribute to the antinociceptive effects of 
paracetamol at a spinal level (1, 2, 3). It presents a lower number of toxic effects in the GI tract compared to 
NSAIDs, as constipation, vomiting (initially), nausea and, uncommonly, dry mouth. It can produce, but very rarely, 
thrombocytopenia and leukopenia. Other haematological reactions including agranulocytosis or pancytopenia have 
been reported. It rarely causes bronchoconstriction in asthmatic patients who are sensitive to aspirin. Paracetamol 
produces only a moderate inhibition of COX-1, as reflected in its weak anti-clotting activity and its good 
gastrointestinal safety. At normal therapeutic doses, metabolism is principally hepatic to sulfate and glucuronic 
conjugates, while a small amount is metabolized in the liver by CYP2E1. It has a half-life of elimination in adults of 
approximately 2 hours, while 3 to 7 hours in pediatric populations, and is excreted principally in urine (4, 5).
Efficacy
Paracetamol, also known as acetaminophen, has been commonly used as an antipyretic as well as analgesic for 
mild to moderate pain relief for approximately 50 years and has relatively few side effects (4). Li Wan published a 
meta-analysis in 1997 that evaluated the efficacy and tolerance of paracetamol against a placebo, finding 15 
randomized control trials. In total, 1144 patients were included, and the difference in grouped means of pain
intensity was 9.4% (6.9% to 11.9%) with a fixed effects model and 9.4% (6.6% to 12.2%) with a randomized model, 
indicating that paracetamol is an effective analgesic based upon this measured effect (6).
In 2013, Moore and Derry published a review analyzing the Efficacy of OTC analgesics; the main sources for this 
review are Cochrane reviews or overviews of the efficacy of analgesics. Regarding acetaminophen the authors 
analyze doses ranging from 500 mg in fixed combinations to 1000 mg as a single substance. The single substance 
use (18 studies with a mixed sample of 2171 patients) show an NNT of 3.3 (3.0-3.7) using a dental pain extraction 
model. In comparison, the authors report a NNT of 4.7 (3.4-7.6) for Acetylsalicylic Acid 1000 mg as a single 
substance (7). This means that in the mentioned doses fewer people have to be treated with Acetaminophen to 
obtain one positive result in post dental surgery pain management. 
Another review, published by Cochrane (Toms et al.) in 2008 analyzes the use of oral paracetamol for 
postoperative pain in adults; this review included randomized, double blind, placebo controlled clinical trials. A 
mixed sample of 3277 patients belonging to 51 studies was analyzed. The reviewed outcomes included patient 
reporting pain at baseline with hourly evaluation over four to six hours, patient global evaluation of treatment, 
rescue medication utilization, withdrawals and adverse events (AE). About half of the patients reported 
improvement of at least 50% over four to six hours (v. 20% in placebo group). The reported NNT for the group of 
patients using a dose of 500 mg of paracetamol was 3.5 (2.7-4.8) and there was no dose response relationship 
(NNT did not change much with higher doses). AE were mostly of mild intensity and the occurrence rate was 
similar to the placebo one. This results show that for an important number of patients, paracetamol is an effective 
and safe way to treat pain (8). 
The role of paracetamol prevails in the treatment of mild acute pain and the management of fever, especially in the 

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pediatric population. For greater pain intensity, paracetamol has been used in combination with other non-steroidal 
anti-inflammatory, or opioids. A review conducted in 1999 by Ward and Alexander-Williams (2) found diverse meta-
analyses in which the combination of paracetamol with opioids presents greater efficacy for the relief of post-
operative pain (3, 6). 
Safety
AE reports for paracetamol are relatively rare. Paracetamol presents a rate of AE that is much lower than other 
pharmaceuticals, such as acetylsalicylic acid, whose gastrointestinal effects (gastrointestinal ulcer and bleeding 
associated with ulcers) are frequent (9). The various studies that have subsequently been done with paracetamol, 
both in humans and in animals, have established this as an analgesic drug with low ulcerogenic capacity (10). The 
principal AE of paracetamol are hepatic and renal toxicity that are produced infrequently, either by suicide or by 
accidental poisoning at high doses (11). A single dose of paracetamol of approximately 6g (12) or more in adults or 
140 mg/kg in children (13) may cause hepatocellular necrosis.
The lethal dose for paracetamol is about 10 g (hepatotoxicity) (14, 15). The symptoms in the first 24-48 hours do 
not reflect the gravity of the hepatic damage. Nausea, vomiting, and abdominal pain can occur initially, but clinical 
signs of hepatic damage take 2-4 days to appear. In serious cases, acute renal insufficiency and coagulopathies 
can present (16).
In the pediatric population, acute ingestion of more than 140mg/kg is associated with hepatotoxicity and death 
when not treated in time. Children under six years of age are relatively less susceptible to toxicity, and tend to have 
a lesser incidence of clinical and biomedical hepatoxicity in levels of paracetamol similar to older children and 
adults (17). 
Hyoscine n-butylbromide 
This is a quaternary antimuscarinic amine derivative of scopolamine. It is used to treat cramps in the 
gastrointestinal, urinary, and uterine tract, as well as biliary ducts and to facilitate the radiologic visualization of the 
gastrointestinal tract. It is principally metabolized in the liver, with an elimination half-life of between 5 and 11 hours, 
and is 42-61% excreted in urine, and 28-37% excreted in stool. (18)
Safety
Due to its low level of absorption, HBB is well-tolerated, presenting few AE. Studies by Schäfer (19) and Mueller-
Lissner (20) compared, in total, 30mg/day of HBB (n=597) with placebo (n=592). There was no significant 
difference in the presence of AE between the two groups, including those effects most commonly associated with 
anticholinergics, such as nausea, constipation, dry mouth, and blurred vision among others. These events occurred 
in less than 1.5% of the participants (21).
In the same way, Herxheimer and Haefeli conducted a study with healthy volunteers who received high doses of 

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HBB (200, 350 and 600mg) without finding the induction of anticholinergic effects (cardiac frequency changes, 
vision changes, or salivary excretion). Additionally, the patients exposed to the highest doses did not present 
central nervous system effects, demonstrating that HBB is safe (18). 
Combination of hyoscine n-butylbromide and Paracetamol
Multiple studies have evaluated the efficacy and safety of the combination of HBB and paracetamol, especially in 
the management of colic-like abdominal pain. Schafer and Ewe conducted a randomized double blind study in 
1990 that involved 712 patients with irritable bowel syndrome. During a treatment period of 4 weeks they 
compared: hyoscine n-butylbromide (30 mg/day) plus paracetamol (1500 mg/day), hyoscine n-butylbromide (30 
mg/day), paracetamol (1500 mg/day) or placebo (3 tablets/day). Patients maintained a record and classification of 
their symptoms (visual analogue scale). At the end of the four weeks 81% of the patients in the group with HBB + 
Paracetamol presented marked or somewhat improvement in symptoms. Statistically significant improvement was 
seen in 76% of the HBB group, 72% in the paracetamol group, and 64% in the placebo group. The daily rating of 
pain in analogue scale showed statistically significant improvement in the intensity of abdominal pain in the group 
with HBB + paracetamol in comparison with the placebo group and the paracetamol group. AE were present in 5% 
of the participants, without differences between the treatment groups, and did not require treatment (19). 
Similar results were reported by Mueller-Lissner et al. when comparing the efficacy and the tolerance of 10 mg of 
HBB, 500mg of paracetamol and their fixed combination in doses three times a day against placebo in patients with 
recurrent colic-type abdominal pain. They found that the three treatments were more effective than the placebo 
related to symptom relief, without differences among these three (20). 
In November 2014, the Peruvian General Direction of Medicines, Supplies and Drugs (DIGEMID) began requiring 
an active pharmacovigilance program in category C products. Additionally, in June 2015 DIGEMID requested that 
all holders of products containing paracetamol in quantities over 325 mg submit an Active Pharmacovigilance Plan.
In order to meet this requirement, Boehringer Ingelheim will conduct active pharmacovigilance by implementing an 
observational prospective cohort study on Buscapina Compositum N to identify, describe, and assess the incidence 
of AE and drug utilization patterns of BUSCAPINA COMPOSITUM N when used in routine, clinical practice, 
according to the label indications in Lima.
Objective(s)
The objectives of this Non-interventional Study (NIS) are to:
1.) Identify and describe the AE and adverse drug reactions (ADR) presented in patients that are undergoing 
treatment with BUSCAPINA COMPOSITUM N in Metropolitan Lima.
2.) Descriptively analyze transaminase levels found by the doctor during the clinical evaluation of patients with 
symptoms related to potential liver damage.
3.) Determine the drug utilization pattern of BUSCAPINA COMPOSITUM N in patients in Metropolitan Lima.
4.) Determine related variables for the occurrence of increase of transaminases in patients under treatment 
with BUSCAPINA COMPOSITUM N in Metropolitan Lima, Peru.
Hypothesis:

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Our hypothesis is that the frequency of AE is no greater than 1.0%
Research Questions:
What AE occur in routine clinical practice in patients that are in treatment with BUSCAPINA COMPOSITUM N
(when it is used according to the label indications)?
What is the incidence of AE and ADR in patients that are in treatment with BUSCAPINA COMPOSITUM N when it 
is used in routine clinical practice according to label indications?
How many patients present with AE symptoms related to a potential liver injury?
What are the drug utilization patterns in patients who receive BUSCAPINA COMPOSITUM N in pharmacies, clinics 
and private doctor’s office in Metropolitan Lima Peru? 
What are the predisposing factors for the occurrence of adverse events and adverse drug reactions in patients who
receive BUSCAPINA COMPOSITUM N in Metropolitan Lima Peru?
Protocol population:
We will include patients 18 years of age and older who attend pharmacies, clinics, or private doctor’s office
in Lima - Peru and who have received at least one dose of BUSCAPINA COMPOSITUM N according to the label 
indications (Patients with any type of gastrointestinal, hepato-biliary, urinary or genital spasmodic syndromes).
Simple size(number of 
subjects to be 
enrolled) 
Since most studies have 
reported a frequency of AE
higher than 1%, to calculate 
the sample size we used 
this percentage as 
reference.
We should therefore enroll 
300 people in order to 
detect up to 2 AE, 
considering an anticipated 
incidence of 0.01 and a 
power of 80%. 
Additionally we will enroll 
60 more patients to offset a 
possible loss to follow up of 
patients of 20%. In total, 
therefore, we will enroll 360 
persons. 
Rationale for the sample size 
(procedure, formula and 
software used) 
To calculate the sample size, we 
have used the following formula for 
cohort studies with no background 
incidence of AE:
The anticipated incidence rate of 
AEs
is 
R0, 
the 
number 
of 
occurrences of a particular AE is A, 
the number of patients is N, and β 
the probability that we will not find 
A events
in the sample of N 
patients. If R0 is small, we may 
assume that the occurrence of an 
AE follow the Poisson distribution. 
The formula shown above is useful 
in determining the values of β, R0, 
A and N. Given that we have the 
values for β, R0 and A, once 
introduced in the formula we obtain 
the result of N (the sample size).

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The sample size was calculated 
using the PASS program version 
11 (www.ncss.com/software/pass).
Number of patients 
according to sex 
(initial number) 
We will enroll both genders in the sample in order to 
reach the desired sample size
Age range for 
subjects to be 
enrolled 
Patients 18 years 
and older.
Inclusion criteria (sex, diagnostic criteria, comorbidities etc.) 
1)
Patients 18 years of age and older who have received at least one dose of BUSCAPINA
COMPOSITUM N according to label indications and who attend to one of the pharmacies,
clinics, or private doctor’s office selected for the study.
2)
Patients who agree to adhere to the protocol procedures of this study.
3)
Women who are not pregnant or breast feeding
4) Persons who sign the informed consent
Exclusion criteria 
1)
Patients with allergy to BUSCAPINA COMPOSITUM N or any of the compounds in the formula.
2)
Patients with mechanical stenosis of the gastrointestinal tract.
3)
Patients with myasthenia gravis.
4)
Patients with megacolon.
5)
Patients breastfeeding at the time of enrollment or who have become pregnant during treatment with
BUSCAPINA COMPOSITUM N.
6)
Patients with clinical evidence of immunosuppression.
7)
Patients with urinary retention subvesical obstruction (such as prostatic adenoma).
8)
Patients with right-angle glaucoma.
9)
Patients with tachycardia and tachyarrhythmia.
10) Patients with severe hepatic impairment.
11) Patients with psychiatric disorders.
12) Patients with alcohol dependence or drugs.
13) Patients who discontinue the protocol are not eligible for re-enrollment.
14) Researchers, company personnel or their relatives.
Study period
Approximately 12 months
Medical 
specialty (ex 
oncology)
Emergency, General Medicine, Internal 
Medicine, Gastroenterology and any other 
department identified where BUSCAPINA 
COMPOSITUM N is prescribed
Condition under study 
(Classification ICD-
10)
Other and unspecified abdominal pain R10.4
Calculus of bile duct without cholangitis or cholecystitis K80.5
Unspecified renal colic N23
Dysmenorrhoea, unspecified N94.6
City (ies) in which the 
study will be 
conducted 
Lima
Study procedure and data collection (surveys, interviews, home visits, etc) 

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PROTOCOL DESIGN
This is a 12-month active pharmacovigilance, prospective, cohort multicenter study to determine the incidence of 
AE associated to increase of transaminases in patients who have received at least one dose of BUSCAPINA 
COMPOSITUM N  according to label indications.  
We will select approximately 15 patient recruitment centers (Clinics, private doctor´s office and pharmacies). We 
will prioritize the clinics, pharmacies and private doctor’s office with the highest volume of BUSCAPINA 
COMPOSITUM N sales.
Enrollment of Patients and Informed Consent 
All of the patients who attend a pharmacy to buy BUSCAPINA COMPOSITUM N or patients who have been treated 
in Emergency, General Medicine, Internal Medicine, Gastroenterology or any other department, or private practice 
where BUSCAPINA COMPOSITUM N is prescribed will be approached by a trained health person of the Project (a 
nurse technician, a nurse, or a licensed midwife). The health personnel will conduct an informed consent. The 
consent will include all of the information that patients need to know about the study such as protocol objectives, 
the risks and benefits of participating in the study, and the contact information of the principal investigator and co-
investigator whom the participant shall call if they have any question or any AE. It will also include the contact 
number of the IRB.
After reading the informed consent and once the patients’ questions are resolved, the site personnel will ask them if 
they want to participate. If a patient agrees to enter into the study, the investigator or designee and the patient will 
sign an informed consent. The investigator or designee will give a copy of the informed consent to the participant. 
Inclusion and exclusion criteria shall be met before patient enrollment.
Baseline survey
Once a patient has agreed to participate, we will proceed with applying a face to face survey, administered by the 
surveyor, in order to collect demographic data, and information related to the BUSCAPINA COMPOSITUM N 
prescription. This data will include: name, birthdate, gender, race, telephone contact, diagnosis, indication for 
initiation of treatment with BUSCAPINA COMPOSITUM N, date of initiation of treatment, dose regimen prescribed, 
treatment duration (at least one dose), treatment end date, administration route, symptoms prior to initiating 
treatment (it is important to identify possible pre-existing liver injuries), laboratory test results, medical history, itself 
and familial history of liver disease and biliary tract disease, concomitant therapy, alcohol and drug consumption 
history, and name and phone of prescribing doctor. 
For this survey, we will use Open Data Kit Collect (www.opendatakit.org), a mobile application based in Android 
that serves to digitize data collection through formats that automatically include georeferencing data. This 
application has been widely used in epidemiology in the field in various parts of the world for real-time monitoring in 
outbreaks, for example, of influenza (22) and Ebola (23). 
Patient Follow Up
All patients who enter the study will be given a follow up card. In this card we will ask participants to register daily 
whatever symptoms or bothers that he/she may experience. Additionally, we will register their consumption of other 

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concomitant pharmaceuticals or vaccines. The patient alert card will also have the contact information of 
investigators, should the participant wish to contact him. Participant responses will be collected in the Smartphone 
with Open Data Kit collect.
Given that the half-life of the components of BUSCAPINA COMPOSITUM N is from 2-11 hours, we will perform 
follow up to patients until a maximum of 3 days after their final dose of the drug. During follow up with patients, we 
will describe in CRF and Non-Interventional Study AE form the AE that occur, the date of the start of the AE, its 
intensity, the date of its resolution, the treatments that were a result of the AE, how the adverse event was 
resolved, the causal evaluation of the AE medical history information and any relevant laboratory information, 
concomitant medications and the contact information of the attending doctor. 
Drug Utilization Patterns
In order to evaluate drug utilization patterns, both in the baseline survey as well as in the follow-up we will ask How 
have you been instructed to take BUSCAPINA COMPOSITUM N? When did you start to take BUSCAPINA 
COMPOSITUM N? When did you finish taking BUSCAPINA COMPOSITUM N? How many doses per day did you 
receive of BUSCAPINA COMPOSITUM N? Where do you store BUSCAPINA COMPOSITUM N?  
If the participant takes another medication, What is the indication? What is the formulation of that medication 
(capsule, suspension, injectable)? What is the route of administration? What is the start date and stop date of the 
medication, the concentration, dose and frequency?
Registry of Adverse Events
Definition of Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. Whatever adverse change clinically significant in the frequency or intensity of a preexisting 
condition associated temporally with the use of the pharmaceutical will also be considered an AE. We will not 
consider the changes that result in normal growth and development as AE, which do not vary in the frequency of 
severity in respect to expected levels (Example: beginning of menstruation or menopause). All AE will be collected 
from the moment that the participant signs the informed consent document until a maximum of 3 days following the 
last time that the patient used the medication. Such events will be registered in the Non-Interventional Study AE 
form of the study and will be reported to Boehringer Ingelheim Peru S.A.C. within 24 hours/ 1 work day of the 
occurrence of the AE.
Adverse Drug Reaction (ADR)
An ADR is defined as a response to a medicinal product, which is noxious and unintended. Response in this 

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context means that a causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility. Adverse reactions may arise from use of the product within or outside the terms of the 
marketing authorization or from occupational exposure. Conditions of use outside the marketing authorization 
include off-label use, overdose, misuse, abuse and medication errors.
Definition of an overdose
An overdose will be defined as the administration of more than 6 tablets of BUSCAPINA COMPOSITUM N per day. 
Report of an Overdose
We will collect information about any cases of overdose, related or not to the occurrence of an AE. 
Report of Pregnancy/ Breast Feeding Events 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the study, after having 
taken Buscapina Compositum N, the investigator must report any drug exposure during pregnancy, which occurred 
in a female subject or in a partner to a male subject to the Sponsor by means of Part A of the Pregnancy Monitoring 
Form. The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form. 
The report will be forward to Boehringer Ingelheim Peru S.A.C. within 24-hours/1-work day of the confirmed event. 
Serious Adverse Events
We will collect information about all AEs, including serious AE that occur for any participant from the moment that 
the informed consent is signed until 3 days after the participant stops receiving BUSCAPINA COMPOSITUM N, 
whether or not the event is associated with the product under investigation. We will complete follow up with all of 
the participants that present with serious AE to determine the outcomes of the events. The serious AE will be 
registered in the NIS AE form of the study and will be reported to Boehringer Ingelheim Perú S.A.C. who will report
to DIGEMID within 24 hours/ 1 workday from the time of the event’s occurrence. A summary of reporting is in the 
table below.
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the informed consent 
onwards until the end of the study:
Type of Report
Timeline
All SAEs associated with Buscapina Compositum N
immediately within 24 hours
All AEs with fatal outcome in patients exposed to Buscapina Compositum 
N
immediately within 24 hours
All non-serious AEs associated with the Buscapina Compositum N
7 calendar days
All pregnancy monitoring forms
7 calendar days
EVALUATION OF ADVERSE EVENTS
For participants that present with AE we will offer a free evaluation by one of the study’s physicians within 3 days of 
the occurrence of the report. The medical evaluation will be the habitual medical evaluation that the patient could 

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require according to the reported symptoms and detected signs. The evaluation will be given in the same place that 
the patient was attended to. During such evaluation, the physician will evaluate if the medication is definitively 
related, probably related, possibly related, probably not related or definitively not related to the event. In the NIS AE 
form the investigator should define the causality as related or not related. If the patient is taken without study 
supervision to a clinic or emergency, the study physician/supervisor must be informed immediately in order to 
attend the patient and be able to evaluate the situation. This evaluation will be shared with the attending physician 
and will be reported to Boehringer Ingelheim Perú S.A.C. within 24 hours/ 1 workday from the time of the event’s 
occurrence. Causal assessments by Investigator will be based on the Karch Lassagna model (24). As Boehringer 
Ingelheim assessment in NIS is yes or no, in the table below it is summarized how the causality will be matched. 
Karch Lassagna Assessment 
BI Assessment 
Certain
Probable /Likely
Possible 
Conditional, unclassified
Yes, positive relationship 
Not assessable, unclassified
Not reported
Unlikely
Not related
No, not related
The study physician will register the following information:
1.
Maximum Intensity
a.
Light/Minimal: The signs or symptoms are perceived but easily tolerated
b.
Moderate: Sufficient discomfort that interferes with daily activities
c.
Severe: Incapacitating, impeding work or daily activities
2.
Seriousness
2.1 A serious AE is any event that occurs with whatever doses and that implies at least one of the following
situations:
-Causing death
-Risking the life of the participant or putting the participant at risk for imminent death due to the
event that occurred
-Causes a state of permanent or significant disability
-Causes or prolongs an existing hospitalization
-Is a birth anomaly or birth defect
-Is a type of cancer
-Is an accidental or intentional overdose
-Other important medical events that possible do not cause death, nor put at risk the life of the
participant, or do not involve hospitalization can be considered a serious AE if the event puts at risk
the participant and requires a possible medical or surgical intervention in order to avoid one of the
four previously mentioned results.

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3.
Duration
We will register the dates of the beginning and the end of the AE. If it is less than one day, we will indicate
the lapse in time and the appropriate unit of measurement.
4.
Action Taken
Did the AE result in the discontinuation of BUSCAPINA COMPOSITUM N?
5.
Relation to BUSCAPINA COMPOSITUM N
Did BUSCAPINA COMPOSITUM N cause the AE? A qualified physician will determine the probability that
BUSCAPINA COMPOSITUM N was the cause of the AE. For the determination of the causality of the AE
we will use the Karch Lassagna algorithm modified by the Spanish Pharmacovigilance System.
The following criteria will serve as a reference to evaluate the probability of the relation between
BUSCAPINA COMPOSITUM N and the AE:
5.1 Presentation
Is there some evidence that the participant was actually exposed to BUSCAPINA COMPOSITUM N? 
(Medical Record, etc.)
5.2 Time Lapse
Did the AE occur in a reasonable amount of time after the use of BUSCAPINA COMPOSITUM N? The 
start of the AE is compatible with an effect induced by BUSCAPINA COMPOSITUM N?
5.3 Alternative Causes
Is the AE reasonable explained by another etiology such as an underlying illness, other medications or 
other factors of the host, or environmental factors?
5.4 Interruption
Did the participant interrupt the course of BUSCAPINA COMPOSITUM N administration? Did the AE
improve or disappear? If the answer is positive to both questions it is considered a positive interruption. 
5.5 Re-exposure
Was the participant re-exposed to BUSCAPINA COMPOSITUM N? Did the AE reappear or get worse? 
If the answer to both questions is affirmative, it is considered a positive re-exposure. If the answer is 
negative, it is considered a negative re-exposure. 
5.6 Consistency with the profile of BUSCAPINA COMPOSITUM N
Is the clinical and pathological presentation of the AE consistent with previous knowledge of 
BUSCAPINA COMPOSITUM N?
The study’s physician will communicate the evaluation of the relationship using the best clinical criteria, 
taking into account the previously noted criteria. 
Definitively related
Evidence exists of the exposure to BUSCAPINA COMPOSITUM N. The temporal sequence of the start of 
the AE in relation to the administration of BUSCAPINA COMPOSITUM N is reasonable. It is very probable 
that the AE has its explanation in BUSCAPINA COMPOSITUM N use as opposed to another cause. The 
interruption is positive. The re-exposure (if plausible) is positive. The AE follows a consistent pattern with 
what is previously known about BUSCAPINA COMPOSITUM N. 

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Probably related 
There is evidence of the exposure to BUSCAPINA COMPOSITUM N. The temporal sequence of the start 
of the AE in relation to the administration of BUSCAPINA COMPOSITUM N is reasonable. It is very 
probably that the AE has its explanation in BUSCAPINA COMPOSITUM N rather than in another cause. 
The interruption (if occurs) is positive. 
Possibly related
There is evidence of the exposure to BUSCAPINA COMPOSITUM N. The temporal sequence of the start 
of the AE in relation to the administration of BUSCAPINA COMPOSITUM N is reasonable. The AE could 
have been caused by another cause that is as equally probable. The interruption (if occurs) is positive. 
Probably not related 
There is evidence of the exposure to BUSCAPINA COMPOSITUM N. There is another cause that is 
more probable for the AE. The interruption (if occurs) is negative or ambiguous.
Definitely not related
The participant did not receive BUSCAPINA COMPOSITUM N, or the temporal sequence of the start of the 
AE in relation to the administration of BUSCAPINA COMPOSITUM N is not reasonable, or other obvious 
causes exist for the adverse event.
Ethics Committee
We will obtain ethical approval from the ethical committee of the Non-Governmental Organisation (NGO) Via Libre. 
This committee holds a national registration as committee RCEI-32 and its approval is found active on the webpage 
of 
the 
Instituto 
Nacional 
de 
Salud 
(the 
Peruvian 
National 
Institute 
of 
Health) 
(http://www.ins.gob.pe/portal/jerarquia/2/937/busqueda-de-comites-institucionales-de-etica-en-investigacion-
registrados/jer.937) 
Protocol activities table:
2015
2016
Dic
Mar
Abr
May
Jun
Jul
Ago
Set
Oct
Nov
Dic
1
2
3
4
5
6
7
8
9
10
11
IRB approval
X
Patient enrollment
X
x
x
x
x
x
x
x
Patient follow-up
X
x
x
x
x
x
x
x
Data analysis
X
Final study report 
writing
X
Data analysis and interpretation of results 
1. Name of the result:
-Description of AE

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-Incidence of AE
-Frequencies of use types
-Predisposing factors for AE occurrence
2. Statistical method used:
1.
For the first objective of the study a descriptive statistical analysis of frequencies will be conducted for the
adverse events that are discovered.
2.
For the second objective of the study, If data is available the incidence rate will be calculated including in the
numerator the number of cases of people who develop an adverse event, and in the denominator the sum of
the different amounts of person time that each participant in the study contributes.
3. For the third objective, we will complete a descriptive statistical analysis related to the drug utilization patterns
in all patients. and compare patterns between those with and without AE.
4. For the fourth objective, we will conduct a logistic regression analysis to identify risk factors (such as past
medical history, concomitant illnesses, drug utilization factors of the medication, and concomitant treatments)
in patients that present with AE and adverse drug reactions related to treatment with BUSCAPINA
COMPOSITUM N.
Descriptive analysis: 
For the univariate analysis of quantitative variables such as age, dose, and time of product intake, and 
transaminases values (if become available) we will use central tendency and dispersion measures. For the analysis 
of categorical variables such as gender, race, indications for which BUSCAPINA COMPOSITUM N is prescribed, 
physician causality assessment, physician seriousness assessment, among others, we will use frequencies and 
percentages. For the bivariate analysis of categorical variables we will use chi-squared or Fisher exact test. For the 
analysis of quantitative variables, we will use the student T test or Mann-Whitney U test. Analysis will be conducted 
using STATA software version 13.
3. Study period
We will conduct the study in approximately 12 months; this period will include the IRB application, patient
recruitment and follow-up, data analysis and final study report writing. The time between first patient first visit and
last patient last visit will be 8 months.
4. Limitations of the study
Our study has some limitations. First, since we are conducting the study only at pharmacies, clinics (and not
Hospitals) and private doctor´s office, our study cannot be generalized to the whole population who use
BUSCAPINA COMPOSITUM N in Lima. Second, we are conducting a cohort study without a control group, thus we
will not be able to compare the incidence of AE with a group of patients not exposed to BUSCAPINA
COMPOSITUM N. To address this issue we will perform a comparison with the incidence of AE found in other
studies described in the introduction section of this protocol. Additionally, the weekly phone calls to participants to
assess if they have developed an AE will affect the frequency of reporting of AE (compared to the frequency that

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could have been found with spontaneous reporting of AE)
Sponsor  :
Boehringer Ingelheim  Perú S.A.C.
Financial source 
Boehringer Ingelheim  Perú S.A.C.
Executing institution :
Sin Brechas S.A.C.
Date for study start 
March 2016
Estimated date for end of 
study 
December2016
4. INVESTIGATIONAL SITES, PRINCIPAL INVESTIGATOR, ETHICS COMMITEE
Investigational sites 
where the study will be 
conducted (*)
Principal investigator
institutional review board that approves the study 
for the site 
Term
Observat
ions
Name and Surname 
Name of the 
institutional 
review board 
approval 
date 
Expiration date 
Pharmacy chains: 
Boticas InkaFarma, 
Mifarma, Arcángel, 
Boticas y Salud, 
Nortfarma. 
Seguro Social de 
Salud, among 
others.
Clinics: Clínica 
Internacional,
Clínica Médica 
Cayetano Heredia, 
among others. 
private doctor´s 
offices
Independent 
pharmacies such as  
América Salud, 
Corporación 
Boticas Perú, 
Grupo Lives, Ceci 
Farma, Farmacia 
universal, 
Inversiones 
Farmacom, 
Drugstores:  
Droguería Las 
Américas, among 
others.
Vía Libre
Co-Investigadores
5. INFORMATION OF CONTACT PERSONS FOR THE STUDY
NAME and Surname
Email
phone
Type of queries to answer
Queries from 
public in general
administ
rative 
queries
scientific 
queries
X
X
X
X
APPROVAL STATUS (DIGEMID)
Under evaluation(        )approved: (     )
Observed:(     )
REASON FOR 
OBSERVATION: 

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Active Pharmacovigilance. Consists in obtaining information of the safety profile of the medicinal products in a 
systematic way in general regarding a certain medicinal product (or group of medicinal products), or a certain 
disease during an specific timeframe. It allows to determine the frequency of ADR, identification of 
predisposing factors, drug utilization factors etc. 
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