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[product monograph template - standard]PRODUCT MONOGRAPH Modified-Release Capsule, 40 mg (as doxycycline monohydrate) GALDERMA CANADA INC. Date of Preparation: 105 Commerce Valley Dr. W., Suite 300 November 09, 2011 Thornhill, Ontario L3T 7W3 Date of Revision: Submission Control No: 156056 August 30, 2012 Page 1 of 27 Table of Contents
August 30, 2012 Page 2 of 27 PrAPPRILON
Doxycycline Modified-Release Capsule, 40 mg (as doxycycline monohydrate) PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form /
Clinically Relevant Nonmedicinal
Modified-release For a complete listing see Dosage Forms, Composition and Packaging section. INDICATIONS AND CLINICAL USE
APPRILON (doxycycline) modified-release capsule is indicated for the treatment of only
inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect
was demonstrated for generalized erythema (redness) of rosacea.
Pediatrics (<18 years of age):
Safety and efficacy in children below the age of 18 years have not been established.
Geriatrics (≥ 65 years of age):
Clinical studies of APPRILON did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects.
APPRILON (doxycycline) modified-release capsule is contraindicated in • patients who are hypersensitive to this drug, to other tetracyclines, or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section. • women in the second or third trimester of pregnancy, or nursing women August 30, 2012 Page 3 of 27 • infants and children up to the age of 8 years • patients with myasthenia gravis (see WARNINGS AND PRECAUTIONS). WARNINGS AND PRECAUTIONS
APPRILON (doxycycline) modified-release capsules contain doxycycline in a formulation
designed to yield plasma levels below the antimicrobial threshold. APPRILON should not
be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing
the numbers or eliminating microorganisms associated with any bacterial disease.
As with other antibiotics, use of APPRILON may result in overgrowth of non-susceptible
microorganisms, including fungi. If superinfection occurs, APPRILON should be discontinued
and appropriate therapy instituted.
Although not observed in clinical trials with APPRILON, the use of tetracyclines may increase
the incidence of vaginal candidiasis. APPRILON should be used with caution in patients with a
history of or predisposition to candidiasis overgrowth.
Use of doxycycline with other drugs and food:
Use of doxycycline with other drugs or food may lead to drug-drug or drug-food interactions
(see DRUG INTERACTIONS).
Concurrent use of an oral retinoid and doxycycline should be avoided due to reports of
pseudotumor cerebri (see DRUG INTERACTIONS).
Carcinogenesis and Mutagenesis
Doxycycline hyclate was evaluated in a long-term animal study. Increases in benign tumours of
the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma) were noted in
female rats. Evidence of oncogenic activity was obtained in studies with related compounds, i.e.,
oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).
Data from an in vitro assay with Chinese hamster ovary (CHO) cells for potential to cause
chromosomal aberrations suggest that doxycycline hyclate is a weak clastogen (see
APPRILON is not recommended in patients with gastrectomy, gastric bypass surgery, or any
surgeries that bypass or exclude the duodenum, or who are otherwise deemed achlorhydric (see
ACTION AND CLINICAL PHARMACOLOGY).
August 30, 2012 Page 4 of 27 Clostridium difficile-associated disease:
Clostridium difficile-associated disease (CDAD) has been reported with use of many
antibacterial agents, including doxycycline. CDAD may range in severity from mild diarrhea to
fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or
symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon
subsequent to the administration of any antibacterial agent. CDAD has been reported to occur
over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit
overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which
contribute to the development of CDAD. CDAD may cause significant morbidity and mortality.
CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be
initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not
directed against Clostridium difficile. In moderate to severe cases, consideration should be given
to management with fluids and electrolytes, protein supplementation, and treatment with an
antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should
be instituted as clinically indicated, as surgical intervention may be required in certain severe
cases (see ADVERSE REACTIONS).
Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving
oral tetracyclines. Most of the patients experiencing esophagitis and/or esophageal ulceration
took their medication immediately before lying down. Administration of adequate amounts of
fluid along with the capsule is recommended to wash down the capsule to reduce the risk of
Caution should be exercised when administering APPRILON to patients with hepatic
impairment or to those receiving potentially hepatotoxic medicinal products. Doxycycline blood
levels in patients treated with APPRILON are lower than in those treated with conventional
antimicrobial formulations of doxycycline. However, there are no data to support safety in
hepatic impairment at this lower dose.
There have been isolated reports of hypersensitivity reactions in clinical trials. If an allergic
reaction occurs, administration of APPRILON should be discontinued and appropriate therapy
should be initiated.
Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis,
vasculitis and serum sickness have been associated with tetracycline-class antibiotics.
August 30, 2012 Page 5 of 27 Symptoms may be manifested by arthralgia, fever, rash and malaise. In symptomatic patients,
liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the
patient. Use of all tetracycline-class drugs should be discontinued immediately.
Use of APPRILON is contraindicated in patients with myasthenia gravis due to the risk of
worsening of the myasthenia gravis condition.
Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use
of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging
fontanels have been associated with the use of tetracyclines in infants. While both of these
conditions and related symptoms usually resolve after discontinuation of the tetracycline, the
possibility for permanent sequelae exists. Patients should be questioned for visual disturbances
prior to initiation of treatment with APPRILON and should be routinely checked for papilledema
while on treatment.
APPRILON should not be used in patients with ocular manifestations of rosacea (such as ocular
rosacea and/or blepharitis/meibomianitis) as this patient population was not studied in clinical
The anti-anabolic action of tetracyclines may cause an increase in BUN. Studies indicate that
this anti-anabolic effect does not occur with the use of doxycycline in patients with impaired
Bacterial resistance to tetracyclines may develop in patients using APPRILON. Due to the
potential for drug-resistant bacteria to develop during the use of APPRILON, it should only be
used as indicated (see MICROBIOLOGY).
The effect of APPRILON on human fertility is unknown. However, oral administration of
doxycycline hyclate adversely affected fertility and reproductive performance in rats (see
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some
individuals taking tetracyclines. Although this was not observed during clinical studies with
APPRILON, patients should minimize or avoid sun exposure or exposure to artificial sunlight
(tanning beds or UVA/B treatment) while using APPRILON and should discontinue therapy if
phototoxicity/skin erythema occurs. The use of sunscreen and other sun protection measures
August 30, 2012 Page 6 of 27 should be considered by patients taking APPRILON.
Tetracycline class antibiotics are known to cause hyperpigmentation in many organs. Skin and
oral pigmentation has been reported to occur independently of time or amount of drug
administration, whereas other pigmentation has been reported to occur upon prolonged
The use of drugs of the tetracycline class during tooth development (second and third trimester
of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent
discolouration of the teeth (yellow-gray-brown). This adverse reaction is more common during
long-term use of the drug but has been observed following repeated short-term courses. Enamel
hypoplasia has also been reported. Tetracycline drugs, therefore should not be used during tooth
All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula
growth rate has been observed in premature human infants given oral tetracycline in doses of 25
mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.
Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues
and can cause retardation of skeletal development on the developing fetus. Evidence of
embryotoxicity has been noted in animals treated in early pregnancy.
APPRILON should not be used during pregnancy. Doxycycline, like other tetracycline-class
antibiotics, can cause fetal harm when administered to a pregnant woman. If any tetracycline is
used during pregnancy, or if the patient becomes pregnant while taking this drug, the patients
should be apprised of the potential hazard to the fetus.
Use of APPRILON is contraindicated in the second and third trimester of pregnancy when the
teeth are developing.
Use of APPRILON is contraindicated in women while they are breastfeeding due to the risk of
dental discolouration and decreased bone growth in the infant. Low levels of tetracyclines are
excreted in the milk of nursing women.
Pediatrics (<18 years of age):
The safety and efficacy of APPRILON in children below the age of 18 years have not been
studied and therefore use in children is not recommended.
Use of APPRILON is contraindicated in infancy and childhood up to the age of 8 years due to
the risk of dental discolouration and decreased bone growth.
August 30, 2012 Page 7 of 27
Monitoring and Laboratory Tests
In therapy with doxycycline, periodic laboratory evaluations of organ systems, including
hematopoietic, renal and hepatic studies should be performed.
Adverse Drug Reaction Overview
The total number of patients experiencing adverse reactions in clinical trials was 56 (20.8%) for
the APPRILON (doxycycline) modified-release capsule treatment group (N = 269) and 38
(14.2%) for the placebo group (N = 268).
The most frequently reported adverse reactions in the APPRILON treatment group in Phase III
studies were diarrhea (4.1%), headache (2.2%), abdominal pain upper (1.9%), fungal infection
(1.9%), nausea (1.9%), aspartate aminotransferase increased (1.5%) and stomach discomfort
(1.1%). Most adverse reactions were mild or moderate in severity. Only 4.8% of patients treated
with APPRILON discontinued due to an adverse reaction. The most frequent adverse reaction
leading to discontinuation was diarrhea (0.7%).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse drug reaction information
from clinical trials is useful for identifying drug-related adverse events and for approximating
In two controlled clinical trials of adult patients with rosacea, 537 patients received APPRILON
or placebo over a 16-week period. The adverse reactions assessed by the Investigator as
probably or possibly related and reported in at least 1% of the patients treated with APPRILON
in the Phase III studies are listed in Table 1 below.
Table 1 - Adverse Reactions Reported in Phase III Clinical Trials by ≥ 1% of
APPRILON-treated Patients (16 Weeks)
System Organ Class / Preferred
Abdominal pain, upper Stomach discomfort August 30, 2012 Page 8 of 27 Nervous system
Infections and infestations
Fungal infection AST = Aspartate aminotransferase
Less Common Clinical Trial Adverse Drug Reactions (<1%)
The following less common adverse events have been designated by the Investigator as related
(possible, probable) to treatment with APPRILON in clinical trials.
Blood and lymphatic: Anemia.
Cardiovascular: Ventricular extrasystoles, palpitations.
Ear and labyrinth: Vertigo.
Gastrointestinal: Dyspepsia (heartburn), gastrointestinal discomfort, gastrointestinal pain,
gastroesophageal reflux disease, gastritis, vomiting, abdominal discomfort, abdominal pain,
abdominal distension, constipation, dysphagia, loose stool, dry mouth.
General disorders: Malaise, chest pain, aches.
Immune: Bronchospasm, facial edema.
Infections and infestations: Candidiasis, vaginal candidiasis, furuncle (boil), cystitis, upper
respiratory tract infection, influenza, bronchitis.
Injury and poisoning: Sunburn, laceration.
Investigations: Liver function tests abnormal, alanine aminotransferase increased, blood lactate
dehydrogenase increased, weight gain, blood uric acid increase, blood pressure increased.
Metabolism and nutrition: Anorexia.
Musculoskeletal and connective tissue: Muscle cramp, muscle spasm.
Nervous system: Balance disorder, dysgeusia, dizziness, ageusia.
Psychiatric: Depression, anxiety, insomnia.
Renal and urinary tract: Micturition urgency.
Reproductive: Vaginal discharge.
Respiratory, thoracic and mediastinal: Dyspnoea, pharyngolaryngeal pain, asthma.
Skin and subcutaneous tissue: Pruritus, skin burning sensation, dry skin, rash, rosacea,
dermatitis, skin reaction.
Post-Market Adverse Drug Reactions
The following events have been reported since the global launch of APPRILON. These events
have been chosen for inclusion due to either their seriousness and/or frequency of reporting.
Post-market adverse reactions are reported spontaneously from a population of unknown size,
thus estimates of frequency cannot be made.
Blood and lymphatic: Anemia hemolytic autoimmune, leucopenia.
Cardiovascular: Tachycardia, arrhythmia.
Eye disorders: Blurred vision, diplopia.
August 30, 2012
Page 9 of 27 Gastrointestinal: Large intestine perforation, esophageal ulcer, pancreatis.
Infections and infestations: Pseudomembranous colitis, clostridium difficile colitis, clostridial
Investigations: Increased blood bilirubin, liver function tests abnormal.
Musculoskeletal and connective tissue: Myalgia.
Nervous system: Migraine, benign intracranial hypertension.
Skin and subcutaneous tissue: Photosensitivity reaction.
Vascular disorders: Vasculitis necrotising.
Adverse Reactions for Tetracyclines
The following adverse reactions have been observed in patients receiving tetracyclines at higher,
Blood: hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
Ear and labyrinth: tinnitus
Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and
inflammatory lesions (with vaginal candidiasis) in the anogenital region. Rare instances of
esophagitis and esophageal ulcerations have been reported in patients receiving the capsule
forms of the drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or
esophageal ulceration took their medication immediately before lying down.
Hepatic: hepatotoxicity (including hepatic failure, autoimmune hepatitis and cholestasis),
hepatitis (elevation of alanine amintransferase or aspartate aminotransferase values) have been
Immune: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness,
pericarditis, and exacerbation of systemic lupus erythematosus.
Musculoskeletal: arthralgia and myalgia.
Neurological: flushing, headache, bulging fontanels in infants, benign intracranial hypertension
Other: discolouration of the thyroid gland.
Renal toxicity: rise in BUN has been reported and is apparently dose-related (see WARNINGS
Skin: maculopapular and erythematous rashes, photosensitivity skin reactions,
photoonycholysis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis,
exfoliative dermatitis have been reported.
Drug-drug interaction studies with APPRILON (doxycycline) modified-release capsules have not
been conducted. The recommendations below regarding the potential interactions between
doxycycline and other medications are based upon experience with higher doses of doxycycline
generally used in antimicrobial formulations.
August 30, 2012 Page 10 of 27 Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors,
antacids containing aluminum, calcium or magnesium and iron-containing preparations.
Therefore, such medicines should be taken after a period of 2 to 3 hours following ingestion of
Quinapril may reduce the absorption of doxycycline due to the high magnesium content in
quinapril tablets. Quinapril, therefore, should be taken after a period of 2 to 3 hours following
ingestion of APPRILON.
Rifampicin, barbiturates, carbamazepine, diphenylhydantoin, primidone, phenytoin and chronic
alcohol abuse may accelerate the metabolism of doxycycline due to enzyme induction in the
liver, thereby decreasing its half-life. Sub-therapeutic doxycycline concentrations may result.
Concurrent use of cyclosporin has also been reported to decrease the half-life of doxycycline.
There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated
with the concomitant use of oral retinoids and tetracyclines. The concurrent use of an oral
retinoid and doxycycline should therefore be avoided.
Bacteriostatic drugs including doxycycline may interfere with the bacteriocidal action of β-
lactam class antibiotics including penicillin. Concurrent use of β-lactam class antibiotics and
doxycycline should be avoided.
Doxycycline has been shown to depress plasma prothrombin activity. Patients who are on
anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
Tetracyclines may interfere with the effectiveness of low dose oral contraceptives. To avoid
contraceptive failure, a second form of contraceptive may be advised during treatment with
The concurrent use of tetracyclines and methoxyfluorane has been reported to result in fatal renal
Doxycycline has been shown to potentiate the hypoglycemic effect of sulphonylurea oral
antidiabetic agents. If administered in combination with these medicinal products, blood glucose
levels should be monitored and, if necessary, the doses of the sulphonylureas should be reduced.
The ingestion of food delayed and reduced the rate and extent of absorption of APPRILON
capsules (see ACTION AND CLINICAL PHARMACOLOGY - Absorption). This decrease in
systemic exposure can be clinically significant, and therefore it is recommended that APPRILON
be taken at least one hour prior to or two hours after the meal (see DOSAGE AND
ADMINISTRATION - Recommended Dose and Dosage Adjustment).
The absorption of doxycycline may be inhibited by bi- or tri-valent ions such as aluminum, zinc,
calcium (found for example in dairy products and calcium-containing fruit juices), therefore
August 30, 2012 Page 11 of 27 these foods should be taken 2 to 3 hours following ingestion of doxycycline.
Interactions with herbal products have not been established.
False elevations of urinary catecholamine levels may occur due to interference with the
All patients receiving doxycycline, including APPRILON, should be advised to minimize or
avoid sunlight or artificial ultraviolet light (see WARNINGS AND PRECAUTIONS – Skin).
Use of sunscreen or sunblock should be considered.
DOSAGE AND ADMINISTRATION
The dosage of APPRILON (doxycycline) modified-release capsules differs from that of
doxycycline used to treat infections. Exceeding the recommended dosage may result in an
increased incidence of side effects including the development of resistant organisms.
Efficacy and safety of APPRILON for the treatment of rosacea beyond 16 weeks have not been
Recommended Dose and Dosage Adjustment
One APPRILON capsule (40 mg, modified-release) should be taken once daily in the morning,
on an empty stomach, preferably at least one hour prior to or two hours after the meal.
Pediatrics (<18 years of age):
APPRILON has not been evaluated in pediatric subjects. The use of doxycycline is
contraindicated in children up to the age of 8 years.
APPRILON is not recommended in patients with gastrectomy, gastric bypass surgery or any
surgeries that bypass or exclude the duodenum, or who are otherwise deemed achlorhydric (see
ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics).
If a single dose of APPRILON is missed, that daily dose should be skipped and the patient
should be instructed to take the next dose at the regular time.
August 30, 2012 Page 12 of 27 Administration
Administration of adequate amounts of fluid along with the capsule is recommended to
wash down the APPRILON capsule to reduce the risk of esophageal irritation and
ulceration (see WARNINGS AND PRECAUTIONS – Gastrointestinal).
For management of a suspected drug overdose, contact your regional Poison Control Centre. No cases of overdose have been reported during clinical trials with APPRILON (doxycycline) modified-release capsules. In the case of overdosage, the medication should be discontinued and the patient should be treated symptomatically. Dialysis does not alter doxycycline pharmacokinetics and therefore would not be of benefit in treating cases of overdose. ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
The pathophysiology of the inflammatory lesions of rosacea is, in part, a manifestation of a
neutrophil-mediated process. Doxycycline has been shown to inhibit neutrophil activity and
several pro-inflammatory reactions including those associated with phospholipase A2,
endogenous nitric oxide and interleukin-6. The clinical significance of these findings is not
APPRILON modified-release capsules are not bioequivalent to other doxycycline products. The
pharmacokinetics of doxycycline following oral administration of APPRILON was investigated
in two studies involving 61 adults. Pharmacokinetic parameters for APPRILON following single
oral doses and at steady-state (7 consecutive days) in fasting healthy subjects are presented in
Table 2 below.
Table 2 - Summary of APPRILON's Pharmacokinetic Parameters
Single dose 40 mg
Steady state*** 40 mg
*Mean ±SD, **Median (range), ***Day 7 The plasma concentration of doxycycline following administration of APPRILON was well below the level required to inhibit microorganisms commonly associated with bacterial disease. August 30, 2012 Page 13 of 27
Doxycycline is almost completely absorbed after oral administration. In a single-dose food-
effect study involving administration of APPRILON to healthy volunteers, co-administration
with a 1000 calorie, high-fat, high protein meal that included dairy products reduced the
bioavailability (AUC) of doxycycline from APPRILON by about 20% and reduced the peak
plasma level by 43%, compared to dosing under fasted conditions.
No new distribution studies have been performed with APPRILON since doxycycline is a well-
established drug substance. Doxycycline is lipophilic and widely distributed in the tissues. The
reported volume of distribution varies from 52.6 to 134 L. Information from the literature
indicates that doxycycline is about 80-90% bound to plasma proteins.
No new metabolism studies have been performed with APPRILON since doxycycline is a well-
established drug substance. Major metabolites of doxycycline have not been identified.
However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin decrease the
half-life of doxycycline (for a comprehensive list of enzyme inducers, see DRUG
INTERACTIONS - Drug-Drug Interactions).
Doxycycline is excreted in the urine and faeces as almost unmetabolized drug. Between 29-55%
of an administered dose can be accounted for in the urine within 72 hours.
Special Populations and Conditions
Pediatrics (<18 years of age):
Pharmacokinetic studies have not been conducted in children 18 years old or younger.
Geriatrics (≥ 65 years of age):
Doxycycline pharmacokinetics have not been evaluated in geriatric patients.
The pharmacokinetics of APPRILON were compared in 16 male and 14 female subjects under
fed and fasted conditions. Female subjects had a higher Cmax and AUC than male subjects,
however a subgroup analysis by gender of the Phase 3 clinical studies did not show a gender
difference in clinical outcome.
Studies have shown no significant difference in serum half-life of doxycycline in patients with
normal and severely impaired renal function. Hemodialysis does not alter the serum half-life of
August 30, 2012 Page 14 of 27 Hepatic Insufficiency:
Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.
In a study in healthy volunteers (N=24) the bioavailability of doxycycline is reported to be
reduced at high pH. This reduced bioavailability may be clinically significant in patients with
gastrectomy, gastric bypass surgery or any surgeries that bypass or exclude the duodenum, or
who are otherwise deemed achlorhydric.
STORAGE AND STABILITY
APPRILON (doxycycline) modified-release capsules should be stored at controlled room
temperature (15°C to 30°C). Store in the original package to protect from light.
DOSAGE FORMS, COMPOSITION AND PACKAGING
APPRILON (doxycycline) 40 mg modified-release capsules are available as beige, opaque, hard gelatin capsules imprinted with "GLD 40". Each capsule contains two types of beads that together provide a dose of 40 mg of doxycycline (as doxycycline monohydrate); the immediate-release beads contain 30 mg of doxycycline and the delayed-release beads contain 10 mg of doxycycline. The non-medicinal ingredients in APPRILON (doxycycline) modified-release capsules are hypromellose, methacrylic acid copolymer, opadry beige, sugar spheres, talc and triethyl citrate. APPRILON is available as 14-capsule blister cards packaged in a carton of 2 cards (28 capsules). August 30, 2012 Page 15 of 27 PART II: SCIENTIFIC INFORMATION
doxycycline monohydrate 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12apentahydroxy-6-methyl-1,11-dioxo-, monohydrate,[4S-(4α, 4aα, 5α, 5aα, 6α, l2aα)] or α -6-deoxy-5-hydroxytetracycline Monohydrate Molecular formula: C22H24N2O8•H2O Structural formula: Physicochemical properties: Doxycycline monohydrate is a yellow crystalline powder that dissolves in dilute solutions of mineral acids and in solutions of alkali hydroxides and carbonates. It is slightly soluble in methanol 1% 1M HC1, very slightly soluble in water and in alcohol, and practically insoluble in chloroform and in ether. August 30, 2012 Page 16 of 27 CLINICAL TRIALS
Study demographics and trial design
Table 3 - Summary of patient demographics and trial design for clinical trials in rosacea*
Dosage, route of
Randomized, double- (19 – 90 years) controlled, parallel- placebo once daily - Oral (capsule) - 16 weeks Randomized, double- (286 on therapy) (19 – 82 years) controlled, parallel- placebo once daily - Oral (capsule) Treatment period was (160 off therapy) followed by a 4-week therapy, 4 weeks period off therapy to evaluate the persistence of treatment effect. *Study patients had rosacea (10 to 40 papules and pustules and ≤ 2 nodules)
The following table presents the primary endpoint, which is the mean change in total
inflammatory lesion count from baseline to Week 16 (Table 4).
Table 4 - Study 301 and 302: Mean change in total inflammatory lesion count from baseline
to Week 16 (ITT population)
SD = standard deviation Total inflammatory lesion count included the number of papules, pustules and nodules. aWeek 16 was the last valid observation available on treatment. bp-Value for treatment difference for change from baseline, using the Van Elteren test stratified by pooled centre. August 30, 2012 Page 17 of 27
The following table provides the proportion of treatment responders at Week 16 (Table 5).
Table 5 - Study 301 and 302: Proportion of treatment respondersa at Week 16b (ITT
aTreatment responder was a patient assessed as Clear or Near Clear (defined as one or two papules) at Week 16. bWeek 16 was the last valid observation available on treatment. cp-Value for treatment differences was based on a Cochran-Mantel-Haenszel test stratified by pooled centre. Patients treated with APPRILON (doxycycline) modified-release capsules did not demonstrate significant improvement in erythema when compared to those treated with placebo. DETAILED PHARMACOLOGY
No new animal pharmacodynamic studies have been conducted with APPRILON (doxycycline) modified-release capsules. Doxycycline is a member of the tetracycline class of antibiotics. The plasma concentration of doxycycline following administration of APPRILON (doxycycline) modified-release capsules is below the level required to treat bacterial diseases. In vivo microbiological studies using immediate-release doxycycline (20 mg twice daily) for 6 to 18 months demonstrated no detectable effect on bacterial flora sampled from the oral cavity, skin, intestinal tract and vagina and did not reveal any evidence of increased bacterial resistance. TOXICOLOGY
Toxicology studies included in this section were conducted with doxycycline hyclate (not
August 30, 2012
Page 18 of 27
Single-Dose Toxicity and Repeat-Dose Toxicity
Table 6 - An overview of single-dose and repeat-dose toxicological studies (conducted with
Administration of Dosing
Single-Dose Toxicity Rat Administration of 750 mg/kg was associated with mortality (1 male at day 3); 500 mg/kg did not elicit any deaths or produce any apparent signs Limit test (500 mg/kg): 5M, 5F Repeat-Dose Toxicity Rat 0, 50, 100, 15M, 15F All doses: hair loss 200: slight reduction in liver weights in males 400: post-dose salivation, food consumption slightly reduced in males, slight reduction in liver weights in males 0, 25, 100, 10M, 10F Majority of findings were present at 400 and 600 mg/kg/day, however, there were some changes at all dose levels although the nature of these was minimal or slight at the lower doses. Findings were indicative of discomfort in the abdominal cavity (labored breathing, hunched posture, distended abdomen, subdued behaviour) and this was confirmed in the histopathological findings of the stomach. In one of the male and female early decedents, gastric erosions were found to be a contributing factor to death. Slight reductions were present in weight gain during the first month of the study and at the beginning of the study there was a reduction in food consumption in 400 and 600 mg/kg/day animals. Clinical pathology investigations showed a number of changes in 400 and 600 mg/kg/day animals and a reduction in protein at 25 mg/kg/day upwards. The changes in the red cell August 30, 2012 Page 19 of 27 Species and
Administration of Dosing
parameters may correlate with the apparent suppression of extramedullary hematopoiesis in the spleen which was also lighter in these animals. Terminal observations included decreased heart and spleen weights and increased kidney weights. Histopathological evaluation identified thyroid and adrenal glands, spleen, stomach, duodenum and cecum as target organs. In the thyroid, brown pigment was presented at 25 mg/kg/day upwards. The stomach changes were present at 100 mg/kg/day upwards and at 25 mg/kg/day there was evidence of an increase of minimal submucosal inflammation. Generally well tolerated and produced minimal signs of toxicity at all dose levels. Salivation and vomiting were seen in a few 25 mg/kg/day animals and more frequently in most of the 50 mg/kg/day animals. Histopathological evaluation revealed evidence of kidney lesions at 25 and 50 mg/kg/day. Urea levels were increased in 25 and 50 mg/kg/day animals. Terminal observations included decreased adrenal weights and increased kidney weights. Histopathology findings revealed a dose-related incidence and severity of tubular degeneration/regeneration and interstitial edema of the kidney and evidence of increased mucus production in the stomach. Generally well tolerated and produced minimal signs of toxicity at all dose levels. Salivation and/or vomiting during or immediately after dosing was seen in several animals from all 4 groups but more frequently in the 15 and 30 mg/kg/day groups. Histopathological examination revealed a dose-related increase in the incidence and severity of tubular degeneration/regeneration in the kidney, especially at 15 and 30 August 30, 2012 Page 20 of 27 Species and
Administration of Dosing
mg/kg/day. Dark thyroid gland was observed in 30 mg/kg/day animals. Interstitial edema in the kidneys was observed in 15 and 30 mg/kg/day animals. Brown pigment in the follicular epithelium of the thyroid was observed in 30mg/kg/day animals. F: females; M: males; MTD: Maximum Tolerated Dose
The oral (dietary) administration of doxycycline at 50, 250 and 500 mg/kg/day for up to 18
months in rats resulted in a reduction in liver weight at 250 and 500 mg/kg/day and pigmentation
of the thyroid gland at all dosages. Histopathology revealed that one rat in the 500 mg/kg dose
group had multiple areas of stomach necrosis.
Subchronic oral administration of doxycycline in beagle dogs for up to 11 days at approximately
250 mg/kg/day was associated with marked toxicity. Post-mortem examination of the mortality
indicated a toxic effect in the liver and stomach.
The oral (dietary) administration of doxycycline at 5, 25 or 50 mg/kg doxycycline for up to 12
months in rhesus monkeys was studied. No deaths occurred and no treatment-related changes
were reported in haematology, blood chemistry or urinalysis parameters. Animals in the 50
mg/kg dose group showed fluorescence of bones and teeth under ultraviolet light. Macroscopic
observation of the thyroids revealed brownish discolouration in one animal of the 50 mg/kg dose
group and a similar finding was apparent in animals of the 25 mg/kg dose group.
Histopathological examination of the thyroids confirmed the presence of a brownish pigment in
three animals of the 50 mg/kg dose group.
Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in vitro point
mutation study with mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo
micronucleus assay conducted in CD-1 mice. However, data from an in vitro assay with CHO
cells for potential to cause chromosomal aberrations suggest that doxycycline hyclate is a weak
Positive results in in vitro mammalian cell assays have been reported for related antibiotics
Doxycycline hyclate was assessed for potential to induce carcinogenesis in a study in which the
compound was administered to Sprague-Dawley rats by gavage at dosages of 20, 75, and 200
mg/kg/day for two years. Increases in benign tumours of the mammary gland (fibroadenoma),
uterus (polyp) and thyroid (C-cell adenoma) were noted in females.
August 30, 2012 Page 21 of 27
Noteworthy non-neoplastic findings included brown pigment in the thyroid, observed in all
treated groups. Reduction in bodyweight gain and cystic endometrial hyperplasia in the uterus
was observed in females treated with 200 mg/kg/day. Focal epithelial hyperplasia in the stomach
was observed in males and females treated with 200 mg/kg/day. Catarrhal exudate and
inflammatory cell infiltrate/inflammation in the nasopharynx was observed in males and females
treated with 75 and 200 mg/kg/day.
Evidence of oncogenic activity was obtained in studies with related compounds, i.e.,
oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).
Reproductive and Development Toxicity
In a fertility and reproductive study, five groups of 25 male and 25 female rats were dosed by
oral gavage at dose levels of 0, 50, 100, 250 or 500 mg/kg/day doxycycline hyclate. A similar
control group received purified water. The males were dosed for 28 days prior to mating,
throughout the mating period and until the day before necropsy. The females were dosed for 14
days prior to mating, during the mating period and until day 7 of pregnancy. The study
demonstrated that the oral administration of doxycycline hyclate to Sprague-Dawley rats
adversely affected fertility and reproductive performance, as evidenced by increased time for
mating to occur, reduced sperm motility, velocity, and concentration, abnormal sperm
morphology, and increased pre-and post implantation losses. Doxycycline induced reproductive
toxicity at all dosages in the study, as even the lowest dose tested (50 mg/kg per day) induced a
statistically significant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6
times the amount of doxycycline contained in the recommended daily dose of APPRILON
(doxycycline) modified-release capsules for a 60-kg human when compared on the basis of area
under the curve (AUC) estimates.
No embryo-fetal development study was performed with doxycycline. However, doxycycline is
known to cross the placenta and literature data indicate that tetracyclines can have toxic effects
on the developing fetus.
In a study for effects on prenatal and postnatal development, including maternal function, five
groups of 25 pregnant female rats (F0 generation) were treated with doxycycline hyclate at dose-
levels of 0, 50, 100, 250 or 500 mg/kg/day. Females were dosed once daily, by oral gavage,
from day 18 of pregnancy (rather than day 7 when implantation occurs as recommended in the
guidance) and throughout lactation until day 20 post-partum, inclusive. The F1 offspring were
not mated to assess reproductive performance. The daily oral administration of doxycycline
hyclate elicited maternal toxicity at 500 mg/kg/day, which included noisy breathing, a reduction
in bodyweight gain, a reduction in food consumption and an increased duration of gestation.
There was also evidence of slight toxicity in the F1 generation, which was characterized by a
reduction in bodyweight during lactation and post-weaning, generalized pallor and an increase in
the numbers of litters containing one or more pups with clinical signs including hair-loss,
piloerection and abnormal hair growth. At 250 mg/kg/day, there was evidence of slight maternal
toxicity (e.g., reduction in bodyweight gain and food consumption, slight increase in the duration
of gestation) and slight toxicity in the F1 generation (e.g., increase in the numbers of litters
August 30, 2012 Page 22 of 27 containing one or more pups with clinical signs including hair-loss, piloerection and abnormal hair growth). At 100mg/kg/day, there was an increase in the numbers of pups with hair-loss in the F1 generation but there was no apparent evidence of maternal toxicity at 100 or 50 mg/kg/day or toxicity in the F1 generation at 50 mg/kg/day. August 30, 2012 Page 23 of 27 REFERENCES
1. Del Rosso JQ, Webster G, Jackson M, Rendon M, Rich P, Torok H, MD, Bradshaw M. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791-802. 2. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol. 1992;44(6):1165-70. August 30, 2012 Page 24 of 27 IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
• You are allergic to any of the ingredients in APPRILON. • You are pregnant, planning to become pregnant or if you are PrAPPRILON
Doxycycline Modified-Release Capsule, 40 mg
• You have been diagnosed with myasthenia gravis (a chronic (as doxycycline monohydrate)
disease which can cause muscle weakness). • You have difficulty swallowing, or medical conditions such This leaflet is part III of a three-part "Product Monograph"
as a narrowing or blockage in your esophagus (passage from published when APPRILON was approved for sale in Canada
your mouth to stomach). and is designed specifically for Consumers. This leaflet is a
• You have liver or kidney problems. summary and will not tell you everything about APPRILON.
• You have or have recently had a yeast or fungus infection in Contact your doctor or pharmacist if you have any questions
your mouth or vagina. about the drug.
• You are taking other prescription medications or other medications, including medications purchased without a prescription, such as vitamin or mineral supplements. ABOUT THIS MEDICATION
• You have had a gastrectomy or gastric bypass surgery. • You spend time in sunlight or artificial sunlight (such as a What the medication is used for:
tanning bed). APPRILON may increase the severity of APPRILON is used for the treatment of bumps and pimples caused sunburns. Avoid sunlight or exposure to artificial UV light. by rosacea (roh-ZAY-she-ah) in adults. This medication should Use a good sunscreen (SPF 15 or higher) and wear not be used for any other reason than that which it is prescribed. protective clothing, such as a hat or sunglasses. What it does:
Tell your doctor or pharmacist right away and stop taking
APPRILON has anti-inflammatory properties that reduce the APPRILON if:
bumps and pimples caused by rosacea. • You develop a hypersensitivity (allergic) reaction which may include symptoms such as difficulty in breathing, fast When it should not be used:
heartbeat, dizziness, itching, rash, and skin blistering. • If you are allergic to the medicinal ingredient in APPRILON, or allergic to any medicinal ingredients known as tetracyclines, including doxycycline and minocycline. INTERACTIONS WITH THIS MEDICATION
• If you are allergic to any of the ingredients in APPRILON (see What the important nonmedicinal ingredients are:).
Drugs that may interact with APPRILON include:
If you are pregnant or nursing. Low levels of tetracyclines • A medication for hypertension, quinipril. are released in human breast milk. • Blood thinners (oral anticoagulants). Your doctor may need In infants and children under 8 years of age. to change your anticoagulant dose. If you have myasthenia gravis (a chronic disease which can • Oral retinoids, such as isotretinoin and acitretin. cause muscle weakness). • Medications that treat infections, such as penicillin and APPRILON should not be used to treat infections.
• Medications that treat seizures, such as barbiturates, What the medicinal ingredient is:
carbamazepine and diphenylhydantoin. APPRILON capsules contain the active ingredient doxycycline (as doxycycline monohydrate). Chronic alcohol abuse may cause APPRILON to break down more quickly and make the medication less effective. What the important nonmedicinal ingredients are:
Proton pump inhibitors (to reduce stomach acidity) such as Each APPRILON capsule is made of gelatin and contains omeprazole, pantoprazole, rabeprazole. hypromellose, methacrylic acid copolymer, opadry beige (for Antacids and dairy products (that contain aluminum, zinc, colour), sugar spheres, talc and triethyl citrate. calcium or magnesium), and bismuth subsalicylate may reduce the absorption of the medicinal ingredient in What dosage forms it comes in:
APPRILON is available in modified-release capsules containing • Products that contain iron should be taken at a different time 40 mg of doxycycline (as doxycycline monohydrate). Each capsule contains two types of beads; the immediate-release beads • The use of APPRILON may reduce the effectiveness of birth contain 30 mg of doxycycline and the delayed-release beads control pills (oral contraceptives). contain 10 mg of doxycycline.
• Some anesthetics/inhalants (e.g. methoxyflurane). • Some medications for diabetes (e.g. sulfonylureas) WARNINGS AND PRECAUTIONS
PROPER USE OF THIS MEDICATION
BEFORE you use APPRILON talk to your doctor or
August 30, 2012 Page 25 of 27 IMPORTANT: PLEASE READ
Usual adult dose:
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
APPRILON should be taken once daily in the morning, on an HAPPEN AND WHAT TO DO ABOUT THEM
empty stomach. It is recommended that the capsule be swallowed with a full glass of water to avoid potential irritation to the esophagus (passage from mouth to stomach). Symptom / effect
Talk with your
Antacids (containing calcium, aluminum or zinc) and foods containing calcium should only be taken at least 2-3 hours after Darkening of
taking APPRILON. teeth or gums.
Do not take more capsules than your doctor has told you to. migraine or
Taking more than the prescribed dose may increase the chance of dizziness
This is not a complete list of side effects. A complete listing of
In case of drug overdose, contact a health care practitioner, adverse events that have been reported is contained in the
hospital emergency department or regional Poison Control Product Monograph supplied to your doctor and pharmacist.
Centre immediately, even if there are no symptoms. For any unexpected effects while taking APPRILON, contact
your doctor or pharmacist.
If you miss a dose of APPRILON, skip that dose and take the next dose at your regular time. Do not double dose. HOW TO STORE IT
Store APPRILON capsules between 15° and 30°C. Store in
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
the original package. Keep the package away from direct
heat and sunlight.
Common side effects include diarrhea, headache, nausea, and Keep your APPRILON capsules in a safe place where
abdominal pain. Some people may experience soreness in the nose children cannot reach them.
or throat (nasopharyngitis), sinus infection or an increase in blood pressure (hypertension). These side effects are generally mild and Do not take APPRILON capsules after the expiry date.
do not usually cause patients to stop taking APPRILON. If you experience symptoms such as severe (watery or bloody) REPORTING SUSPECTED SIDE EFFECTS
diarrhea, fever, abdominal pain or tenderness, you may have Clostridium difficile colitis (bowel inflammation). If this happens, You can report any suspected adverse reactions associated with
stop taking the drug and call your healthcare professional the use of health products to the Canada Vigilance Program by
one of the following 3 ways:
Report online at www.healthcanada.gc.ca/medeffect
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
Call toll-free at 1-866-234-2345
HAPPEN AND WHAT TO DO ABOUT THEM
Complete a Canada Vigilance Reporting Form and:
- Fax toll-free to 1-866-678-6789, or
Symptom / effect
Talk with your
- Mail to: Canada Vigilance Program
Postal Locator 0701D
Postage paid labels, Canada Vigilance Reporting Form
and the adverse reaction reporting guidelines are
available on the MedEffect™ Canada Web site at
NOTE: Should you require information related to the management
of side effects, contact your health professional. The Canada
Vigilance Program does not provide medical advice.
tightness in the
August 30, 2012 Page 26 of 27 IMPORTANT: PLEASE READ
This document plus the full product monograph, prepared for health professionals can be found at: www.galderma.ca or by contacting the sponsor, Galderma Canada Inc. at: 1-800-467-2081 This leaflet was prepared by Galderma Canada Inc. Last revised: August 30, 2012 August 30, 2012 Page 27 of 27
SCHERING CORP. v. GENEVA PHARMACEUTICALS Cite as 339 F.3d 1373 (Fed. Cir. 2003) the parties intended that all files that were 1. Federal Courts O766 officially kept would be purged as agreed. Grant of summary judgment is re- viewed without deference. 2. Patents O72(1) Patent is invalid for anticipation if sin-
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