Minolira
(minocycline)Minolira Prescribing Information
MINOLIRA is indicated to treat the inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.
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)].
The recommended dosage of MINOLIRA is approximately 1 mg/kg once daily for 12 weeks. Higher doses have not shown to be of additional benefit in the treatment of inflammatory lesions of acne, and may be associated with more acute vestibular side effects. The 105 mg and 135 mg tablets may be split on the score line for dosing of patient weight ranges of 45-59 kg and 60-89 kg, respectively (see Table 1).
| Patient's Weight (kg) | Daily Dose | Tablet Strength and Size to Administer | Actual Dose (mg/kg) |
|---|---|---|---|
| 45 – 59 | 52.5 | half of the 105 mg tablet | 1.16 –0.88 |
| 60 – 89 | 67.5 | half of the 135 mg tablet | 1.13 – 0.76 |
| 90 – 125 | 105 | one 105 mg tablet | 1.17 – 0.84 |
| 126 – 136 | 135 | one 135 mg tablet | 1.07 – 0.99 |
MINOLIRA may be taken with or without food [see Clinical Pharmacology (12.3)]. Ingestion of food along with MINOLIRA may help reduce the risk of esophageal irritation and ulceration. MINOLIRA tablets should not be chewed or crushed.
In patients with renal impairment, the total dosage should be decreased by either reducing the recommended individual doses and/or by extending the time intervals between doses [see Warnings and Precautions (5.6)].
MINOLIRA extended-release tablets are white to off-white, functionally scored, rectangular tablets with brown or gold color speckles and a single score line on both surfaces. MINOLIRA are available in the following two strengths.
- 105 mg extended-release tablets: ‘M1’debossed on one surface, where ‘M’ and ‘1’ are on either side of the score line. Each tablet contains 105 mg minocycline, equivalent to 113.4 mg of minocycline hydrochloride.
- 135 mg extended-release tablets: ‘M3’ is debossed on one surface, where ‘M’ and ‘3’ are on either side of the score line. Each tablet contains 135 mg minocycline, equivalent to 145.8 mg of minocycline hydrochloride.
Pregnancy
Risk Summary
MINOLIRA, like tetracycline class drugs, may cause permanent discoloration of teeth and reversible inhibition of bone growth when administered during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. Post-marketing cases of minocycline use in pregnant women report congenital anomalies such as limb reductions. The limited data are not sufficient to inform a drug-associated risk for birth defects or miscarriage. In animal reproduction studies, minocycline induced skeletal malformations in fetuses when orally administered to pregnant rats and rabbits during the period of organogenesis at systemic exposure of approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients administered MINOLIRA (see Data). If a patient becomes pregnant while taking this drug, advise the patient of the risk to the fetus and discontinue treatment.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Human Data
The use of tetracycline during tooth development (second and third trimesters of pregnancy) may cause permanent discoloration of deciduous teeth. This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses.
Animal Data
Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development of the developing fetus. [see Warnings and Precautions (5.1)].
Minocycline induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits during the period of organogenesis at doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (resulting in approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients administered MINOLIRA). Reduced mean fetal body weight was observed when minocycline was administered to pregnant rats during the period of organogenesis at a dose of 10 mg/kg/day (which resulted in approximately the same level of systemic exposure to minocycline as that observed in patients administered MINOLIRA).
Minocycline was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation , at doses of 5, 10, or 50 mg/kg/day. In this study, body weight gain was significantly reduced in pregnant females that received 50 mg/kg/day (resulting in approximately 2.5 times the systemic exposure to minocycline observed in patients administered MINOLIRA). No effects of treatment on the duration of the gestation period or the number of live pups born per litter were observed. Gross external anomalies observed in F1 pups (offspring of animals that received minocycline) included reduced body size, improperly rotated forelimbs, and reduced size of extremites. No effects were observed on the physical development, behavior, learning ability, or reproduction of F1 pups, and there was no effect on gross appearance of F2 pups (offspring of F1 animals).
Lactation
Risk Summary
Tetracycline-class drugs including minocycline are present in breast milk. It is not known whether minocycline has an effect on the breastfed infant or on milk production. Because of the potential for serious adverse effects on bone and tooth development in breastfed infants from the tetracycline-class drugs, advise a woman that breastfeeding is not recommended with MINOLIRA therapy [see Warnings and Precautions (5.1)].
Females and Males of Reproductive Potential
Contraception
MINOLIRA may reduce the effectiveness of low-dose oral contraceptives. Patients of reproductive potential should not rely on low-dose oral contraceptives as an effective contraceptive method, and should use an additional method of contraception during treatment with MINOLIRA [see Drug Interactions (7.4)].
Infertility
Avoid using MINOLIRA in males who are attempting to conceive a child. Limited human studies suggest that minocycline may have a deleterious effect on spermatogenesis. In a fertility study in rats, minocycline adversely affected spermatogenesis when orally administered to male rats at doses resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients administered MINOLIRA [see Nonclinical Toxicology (13.1)].
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.
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.
MINOLIRA is contraindicated in patients who have shown hypersensitivity to any of the tetracyclines [see Serious Skin/Hypersensitivity Reactions (5.11)].
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)].
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.
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)].
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Superinfection
Use of MINOLIRA may result in overgrowth of nonsusceptible organisms, including fungi. If super infection occurs, discontinue MINOLIRA and institute appropriate therapy.
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.