Limitations of Use

This formulation of minocycline has not been evaluated in the treatment of infections.

To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, MINOLIRA should be used only as indicated [see Warnings and Precautions (5.13)].

5.1 Teratogenic Effects

Avoid MINOLIRA use during pregnancy.

MINOLIRA, like other tetracycline-class drugs, can cause fetal harm when administered to a pregnant woman. MINOLIRA, like other tetracycline-class drugs, may cause permanent discoloration of the teeth and inhibit bone growth when administered during pregnancy. Based on animal data, tetracyclines cross the placenta, are found in fetal tissues, and can cause skeletal malformation and retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy. If MINOLIRA is used during pregnancy, advise the patient of the potential risk to the fetus and discontinue treatment [see Use in Specific Populations (8.1)].

5.2 Tooth Discoloration

The use of tetracycline class drugs during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the tetracycline but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use of tetracycline drugs is not recommended during tooth development.

The safety and effectiveness of MINOLIRA have not been established in pediatric patients less than 12 years of age.

5.3 Inhibition of Bone Growth

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. The safety and effectiveness of MINOLIRA have not been established in patients less than 12 years of age [see Use in Specific Populations (8.1, 8.4)].

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 early in pregnancy [see Use in Specific Populations (8.1)].

5.4 Pseudomembranous Colitis

Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including minocycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Hepatotoxicity

Post-marketing cases of serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal) have been reported with minocycline use in the treatment of acne.

5.6 Metabolic Effects

The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class drugs may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable.

5.7 Central Nervous System Effects

Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and usually rapidly disappear when the drug is discontinued.

5.8 Intracranial Hypertension

Intracranial hypertension has been associated with the use of tetracycline-class drugs including MINOLIRA. Clinical manifestations of intracranial hypertension include headache, blurred vision, diplopia and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at a greater risk for developing intracranial hypertension. Concomitant use of isotretinoin and tetracycline should be avoided because isotretinoin, a systemic retinoid, is also known to cause intracranial hypertension.

Although intracranial hypertension typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Because intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize.

5.9 Autoimmune Syndromes

Tetracyclines have been associated with the development of autoimmune syndromes. The long- term use of minocycline in the treatment of acne has been associated with drug-induced lupus- like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness have presented shortly after minocycline use. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, immediately discontinue the use of all tetracycline-class drugs, including MINOLIRA.

5.10 Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines; this reaction has been reported less frequently with minocycline. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using minocycline. If patients need to be outdoors while using MINOLIRA, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

5.11 Serious Skin/Hypersensitivity Reaction

Cases of anaphylaxis, serious skin reactions (e.g. Stevens Johnson syndrome), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported postmarketing with minocycline use in patients with acne. DRESS syndrome consists of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following visceral complications such as: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present. In some cases, death has been reported. If this syndrome is recognized, discontinue MINOLIRA immediately.

5.12 Tissue Hyperpigmentation

Tetracyclines are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as pigmentation over sites of scars or injury.

5.13 Development of Drug-Resistant Bacteria

MINOLIRA has not been evaluated in the treatment of infections.

Bacterial resistance to the tetracyclines may develop in patients using MINOLIRA. Because of the potential for drug-resistant bacteria to develop during the use of MINOLIRA, it should be used only as indicated.

5.14 Superinfection

Use of MINOLIRA may result in overgrowth of nonsusceptible organisms, including fungi. If super infection occurs, discontinue MINOLIRA and institute appropriate therapy.

5.15 Laboratory Monitoring

Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

The following table summarizes selected adverse reactions reported in clinical trials at a rate of ≥1% for minocycline hydrochloride extended release tablets.

6.2 Postmarketing Experience

Adverse reactions that have been reported with minocycline hydrochloride use in a variety of indications include:

Skin and hypersensitivity reactions: fixed drug eruptions, balanitis, erythema multiforme, Stevens-Johnson syndrome, anaphylactoid purpura, photosensitivity, pigmentation of skin and mucous membranes, hypersensitivity reactions, angioneurotic edema, anaphylaxis, DRESS syndrome [see Warnings and Precautions (5.11)].

Autoimmune conditions: polyarthralgia, pericarditis, exacerbation of systemic lupus, pulmonary infiltrates with eosinophilia, transient lupus-like syndrome.

Central nervous system: pseudotumor cerebri, bulging fontanels in infants, decreased hearing.

Endocrine: brown-black microscopic thyroid discoloration, abnormal thyroid function.

Oncology: thyroid cancer.

Oral: glossitis, dysphagia, tooth discoloration.

Gastrointestinal: enterocolitis, pancreatitis, hepatitis, liver failure.

Genitourinary: Preliminary studies suggest that use of minocycline may have deleterious effects on human spermatogenesis [see Nonclinical Toxicoloty (13.1)].

Renal: reversible acute renal failure.

Hematology: hemolytic anemia, thrombocytopenia, eosinophilia.

7.1 Anticoagulants

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

7.2 Penicillin

Because bacteriostatic drugs may interfere with the bactericidal action of penicillin, to avoid giving tetracycline-class drugs in conjunction with penicillin.

7.3 Antacids and Iron Preparations

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and iron-containing preparations.

7.4 Low Dose Oral Contraceptives

In a multi-center study to evaluate the effect of minocycline extended release tablets on low dose oral contraceptives, hormone levels over one menstrual cycle with and without minocycline extended release tablets 1 mg/kg once-daily were measured. Based on the results of this trial, minocycline-related changes in estradiol, progestinic hormone, FSH and LH plasma levels, of breakthrough bleeding, or of contraceptive failure, cannot be ruled out. To avoid contraceptive failure during treatment with minocycline, advise patients of reproductive potential to use a second form of contraception in addition to low-dose oral contraceptives.

7.5 Drug/Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of MINOLIRA have been established in pediatric patients 12 years of age and older for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris [see Pharmacokinetics (12.3) and Clinical Studies (14)]. Tooth discoloration and inhibition of bone growth have been observed in pediatric patients [see Warnings and Precautions (5.2, 5.3)]. The safety and effectiveness of MINOLIRA have not been established in pediatric patients less than 12 years of age.

8.5 Geriatric Use

Clinical studies of MINOLIRA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

12.1 Mechanism of Action

The mechanism of action of MINOLIRA for the treatment of acne is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of MINOLIRA for the treatment of acne are unknown.

12.3 Pharmacokinetics

The pharmacokinetics of minocycline following oral administration of a single dose of MINOLIRA (135 mg) was investigated in 77 healthy male and female adult subjects under fasting conditions. The pharmacokinetic parameters of minocycline under fasting conditions are presented in Table 3.

In a separate trial, a single dose of MINOLIRA (135 mg) was administered orally with a high-fat, high-calorie meal that included dairy products to 36 healthy male and female adult subjects. The estimated calorie content of the meal was 848 Kcal, consisting of 145 Kcal from protein, 250 Kcal from carbohydrates, and 453 Kcal from fat. The pharmacokinetic parameters of minocycline under fed conditions are presented in Table 4.

Minocycline is lipid soluble and distributes into the skin and sebum.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female rats once daily for up to 104 weeks at dosages up to 200 mg/kg/day, minocycline hydrochloride was associated in both genders with follicular cell tumors of the thyroid gland, including increased incidences of adenomas, carcinomas, and the combined incidence of adenomas and carcinomas in males, and adenomas and the combined incidence of adenomas and carcinomas in females. In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female mice once daily for up to 104 weeks at dosages up to 150 mg/kg/day, exposure to minocycline hydrochloride did not result in a significantly increased incidence of neoplasms in either males or females.

Minocycline was not mutagenic in vitro in a bacterial reverse mutation assay (Ames test) or CHO/HGPRT mammalian cell assay in the presence or absence of metabolic activation. Minocycline was not clastogenic in vitro using human peripheral blood lymphocytes or in vivo in a mouse micronucleus test.

Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (which resulted in up to approximately 40 times the level of systemic exposure to minocycline observed in patients administered MINOLIRA). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients administered MINOLIRA) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day included a reduced number of sperm cells per gram of epididymis, an apparent reduction in the percentage of sperm that were motile, and (at 100 and 300 mg/kg/day) increased numbers of morphologically abnormal sperm cells. Morphological abnormalities observed in sperm samples included absent heads, misshapen heads, and abnormal flagella.

How Supplied

MINOLIRA is supplied as functionally scored extended-release tablets containing minocycline hydrochloride equivalent to 105 mg and 135 mg of minocycline.

The 105 mg extended-release tablets are white to off-white, rectangular, with brown or gold color speckles. The tablets have a single score line on both surfaces and are debossed with ‘M1’ on one surface. On the face with debossing, ‘M’ and ‘1’ are on either side of the score line. Each tablet contains 26.25 mg of minocycline as immediate release beads and 78.75 mg of minocycline as extended release beads. The 105 mg tablets are supplied as follows:

The 135 mg extended-release tablets are white to off-white, rectangular with brown or gold color speckles. The tablets have a single score line on both surfaces and are debossed with ‘M3’ on one surface. On the face with debossing, ‘M’ and ‘3’ are on either side of the score line. Each tablet contains 33.75 mg of minocycline as immediate release beads and 101.25 of minocycline as extended release beads. The 135 mg tablets are supplied as follows:

Storage

Store at 20°C - 25°C (68°F - 77°F); excursions are permitted to 15°C-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

Teratogenic effects

• Advise patients to avoid use of MINOLIRA during pregnancy.
• Advise patients that MINOLIRA use during pregnancy may cause inhibition of fetal bone growth.
• Advise patients that MINOLIRA use during pregnancy may cause discoloration of deciduous teeth.
• Advise patients to discontinue MINOLIRA during pregnancy.

Tooth Discoloration

• Advise caregivers of pediatric patients that MINOLIRA use may cause permanent discoloration of deciduous and permanent teeth.

Lactation

• Advise a woman that breast feeding is not recommended during MINOLIRA therapy.

Contraception

• Advise patients of reproductive potential that MINOLIRA may reduce the effectiveness of low-dose oral contraceptives. Advise patients of reproductive potential not rely on low-dose oral contraceptives as an effective contraceptive method and to use an additional method of contraception during treatment with MINOLIRA.

Infertility

• Advise males of reproductive potential that MINOLIRA may impair fertility.

Tissue Hyperpigmentation

• Inform patients that MINOLIRA may cause discoloration of skin, scars, teeth or gums.

Pseudomembranous Colitis

• Advise patients that pseudomembranous colitis can occur with minocycline therapy, including MINOLIRA. Advise patients to seek medical attention if they develop watery or bloody stools.

Hepatotoxicity

• Inform patients about the possibility of hepatotoxicity. Advise patients to seek medical advice if they experience symptoms or signs of hepatotoxicity, including loss of appetite, tiredness, diarrhea, jaundice, increased bleeding tendencies, confusion, and sleepiness.

Central Nervous System Effects

• Inform patients that central nervous system adverse reactions including dizziness or vertigo have been reported with minocycline therapy. Caution patients about driving vehicles or using hazardous machinery if they experience such symptoms while on MINOLIRA.

Intracranial Hypertension

• Inform patients that intracranial hypertension can occur with minocycline therapy. Advise patients to seek medical attention if they develop unusual headache, visual symptoms, such as blurred vision, diplopia, and vision loss.
• Inform patients that autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with tetracycline-class drugs, including minocycline. Symptoms may be manifested by arthralgia, fever, rash and malaise.
• Advise patients who experience such symptoms to stop the drug immediately and seek medical help.

Photosensitivity

• Inform patients that photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline.
• Advise patients to minimize or avoid exposure to natural or artificial UV light (tanning beds or UVA/B treatment) while using MINOLIRA.
• Discuss other sun protection measures, if patients need to be outdoors while using MINOLIRA.
• Advise patients to discontinue treatment at the first evidence of sunburn.

Important Administration Instructions

• Inform patients to take MINOLIRA as directed. Missing doses or not completing the full course of therapy may decrease the effectiveness of the current treatment course and increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future.
• Advise patient not to chew or crush the tablet.
• Advise patients to split MINOLIRA tablet across the score line, if required depending on patient's body weight.