Doxycycline (Modified-Release) (Apprilon)

1. Health Canada Product Monograph — Doxycycline (Modified-Release)

• Apprilon is indicated for the treatment of only the inflammatory lesions (papules and pustules) of rosacea in adults. No meaningful effect was demonstrated for generalized redness (erythema) of rosacea.
• It has not been studied in patients with ocular manifestations of rosacea (ocular rosacea, blepharitis/meibomianitis) and should not be used in this population -- standard antimicrobial-dose doxycycline, not Apprilon specifically, is the tetracycline more commonly used for ocular rosacea.
• Efficacy and safety beyond 16 weeks of treatment have not been established.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Contraindicated in the second and third trimester of pregnancy, when fetal teeth are developing -- tetracyclines can cause permanent tooth discolouration and enamel hypoplasia, and can temporarily inhibit fetal bone growth.
• Apprilon should not be used during pregnancy at all. If a patient becomes pregnant while taking it, she should be informed of the potential hazard to the fetus.

• Contraindicated while breastfeeding, due to the risk of dental discolouration and decreased bone growth in the infant; low levels of tetracyclines are excreted into breast milk.

• Clinical trials did not include enough patients aged 65 and older to determine whether they respond differently than younger patients.

• Not evaluated in patients under 18; use in this age group is not recommended.
• Contraindicated in infants and children up to age 8, due to the risk of permanent tooth discolouration and decreased bone growth.

• One 40 mg modified-release capsule once daily in the morning, on an empty stomach -- preferably at least 1 hour before or 2 hours after a meal, since food delays and reduces absorption.
• Take with an adequate amount of fluid to wash the capsule down and reduce the risk of esophageal irritation/ulceration; avoid lying down immediately after taking it.
• Do not exceed the recommended dose -- this is a fixed anti-inflammatory dose, and exceeding it risks both increased side effects and pushing plasma levels into the antibacterial range, promoting resistance.
• Not recommended in patients with a history of gastrectomy, gastric bypass, or other surgery that bypasses/excludes the duodenum, or who are otherwise achlorhydric, since absorption depends on normal gastric acidity.
• If a dose is missed, skip it and take the next dose at the regular time -- do not double up.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• No overdose cases have been reported in Apprilon clinical trials. In case of overdose, discontinue the medication and treat symptomatically. Dialysis does not alter doxycycline pharmacokinetics and would not be expected to help. Contact your regional Poison Control Centre for any suspected overdose.

• Diarrhea (most common, about 4% of patients), headache, upper abdominal pain, fungal infection (e.g., vaginal candidiasis), nausea, elevated liver enzymes (AST), and stomach discomfort were the most frequently reported effects in trials.
• Less common: dyspepsia/heartburn, other GI discomfort, dizziness, altered taste, muscle cramps, anxiety, insomnia, and skin reactions such as itching or dry skin.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Clostridioides difficile-associated diarrhea/colitis -- can range from mild diarrhea to severe, life-threatening colitis, and can occur even weeks after stopping the drug.
• Pseudotumor cerebri (benign intracranial hypertension) -- presents as headache and blurred vision; ask about visual disturbances before starting and monitor for papilledema during treatment.
• Esophagitis/esophageal ulceration -- reduced by taking with plenty of fluid and not lying down right after the dose.
• Autoimmune reactions (drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis, serum sickness) -- can present with joint pain, fever, rash, and malaise.
• Photosensitivity reaction, permanent tooth/tissue hyperpigmentation (age-dependent), hepatotoxicity, hypersensitivity/anaphylaxis (rare), and blood dyscrasias have been reported, mainly with antimicrobial-dose tetracyclines.
• Seek medical attention for severe or persistent diarrhea, vision changes or severe headache, joint pain with fever and rash, or any sign of a serious allergic reaction.

• Minimize sun and artificial UV (tanning bed) exposure; use sunscreen, and stop at the first sign of a sunburn-like skin reaction.
• Use with caution in hepatic impairment or with other potentially hepatotoxic medications.
• Use with caution in patients with a history of, or predisposition to, candidiasis overgrowth.
• Periodic laboratory monitoring of blood counts, renal, and hepatic function is reasonable during therapy.
• Do not combine with an oral retinoid (e.g., isotretinoin) -- increased risk of pseudotumor cerebri.

• Hypersensitivity to doxycycline, other tetracyclines, or any ingredient in the formulation.
• Second or third trimester of pregnancy, or breastfeeding.
• Infants and children up to age 8.
• Myasthenia gravis -- risk of worsening the condition.

• Absorption is reduced by antacids and supplements containing aluminum, calcium, magnesium, iron, bismuth, or activated charcoal, by sucralfate, and by proton pump inhibitors -- separate administration by 2 to 3 hours.
• Rifampin, barbiturates, carbamazepine, phenytoin, primidone, and chronic alcohol use can accelerate doxycycline metabolism (enzyme induction), potentially producing subtherapeutic levels.
• Cyclosporine has been reported to decrease the half-life of doxycycline -- separate dosing by about 2 hours.
• Avoid combining with an oral retinoid (e.g., isotretinoin) -- risk of pseudotumor cerebri.
• May reduce the bactericidal effect of beta-lactam antibiotics (e.g., penicillins) -- avoid combining.
• Can potentiate the effect of warfarin/other anticoagulants -- monitor coagulation parameters and adjust the anticoagulant dose if needed.
• May reduce the effectiveness of low-dose hormonal contraceptives -- advise a backup method during treatment.
• Can potentiate the hypoglycemic effect of sulfonylureas -- monitor blood glucose and reduce the sulfonylurea dose if needed.

• Food delays and reduces absorption -- take at least 1 hour before or 2 hours after a meal.
• Dairy products and calcium-fortified juices reduce absorption -- separate by 2 to 3 hours from dosing.

• Take once daily in the morning, on an empty stomach.

• Store at controlled room temperature (15°C to 25°C), in the original package, protected from light.

• Apprilon treats the bumps and pimples of rosacea using a low, anti-inflammatory dose of doxycycline -- it is not meant to treat infections, and it will not meaningfully improve facial redness on its own.
• Take it once daily in the morning on an empty stomach, with a full glass of water, and stay upright for a while afterward to protect your esophagus.
• Avoid sun exposure and tanning beds, and use sunscreen, since this medicine increases sun sensitivity.
• This medicine must not be used in pregnancy or while breastfeeding, and is not used in children under 8.
• Contact your doctor promptly for severe diarrhea, vision changes with headache, or any sign of a serious allergic or autoimmune-type reaction.