Sotret

iSotretinoin

Dosage Form: Capsules

CAUSES BIRTH DEFECTS

DO NOT GET PREGNANT

CONTRAINDICATIONS AND WARNINGS

Sotret must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking iSotretinoin capsules in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects which have been documented following iSotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

If pregnancy does occur during treatment of a female patient who is taking iSotretinoin capsules, iSotretinoin capsules must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Special Prescribing Requirements

Because of iSotretinoin’s teratogenicity and to minimize fetal exposure, Sotret is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret capsules must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS).

Table 1 Monthly Required iPLEDGE Interactions

	Female Patients of Childbearing Potential	Male Patients, And Female Patients Not of Childbearing Potential
PRESCRIBER
Confirms patient counseling	X	X
Enters the 2 contraception methods chosen by the patient	X
Enters pregnancy test results	X
PATIENT
Answers educational questions before every prescription	X
Enters 2 forms of contraception	X
PHARMACIST
Calls system to get an authorization	X	X

Sotret Description

ISotretinoin, a retinoid, is available as Sotret in 10 mg, 20 mg, 30 mg, and 40 mg soft gelatin capsules for oral administration. Each capsule contains butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil, hydrogenated vegetable oil, iron oxide black, soybean oil and white wax. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg - iron oxide (red) and titanium dioxide; 20 mg - FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 30 mg - FD&C Yellow No. 6, and titanium dioxide; 40 mg - FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.

Chemically, iSotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A).

It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

Sotret - Clinical Pharmacology

ISotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of iSotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Sotret, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of iSotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of iSotretinoin capsules under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of iSotretinoin were more than doubled following a standardized high-fat meal when compared with iSotretinoin capsules given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of iSotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Sotret capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of iSotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2 Pharmacokinetic Parameters of ISotretinoin Mean (%CV), N=74

ISotretinoin Capsules 2 x 40 mg Capsules	AUC0-∞ (ng•hr/mL)	Cmax(ng/mL)	Tmax(hr)	t1/2(hr)
*Eating a standardized high-fat meal
Fed*	10,004 (22%)	862 (22%)	5.3 (77%)	21 (39%)
Fasted	3,703 (46%)	301 (63%)	3.2 (56%)	21 (30%)

Distribution

ISotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of iSotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-iSotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. ISotretinoin is also irreversibly oxidized to 4-oxo-iSotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of iSotretinoin capsules to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent iSotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of iSotretinoin to adult cystic acne patients (≥ 18 years), the exposure of patients to 4-oxo-iSotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of iSotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in iSotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. ISotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14C-iSotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of iSotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of iSotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of iSotretinoin and 4-oxo-iSotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of iSotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of iSotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥ 18 years) who received iSotretinoin capsules for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-iSotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for iSotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of iSotretinoin between pediatric and adult patients.

Table 3. Pharmacokinetic Parameters of ISotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38*

Parameter	ISotretinoin (Single Dose)	ISotretinoin (Steady-State)
* The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. † Median (range)
Cmax (ng/mL)	573.25 (278.79)	731.98 (361.86)
AUC(0-12) (ng•hr/mL)	3033.37 (1394.17)	5082 (2184.23)
AUC(0-24) (ng•hr/mL)	6003.81 (2885.67)	–
Tmax (hr)†	6.00 (1.00 to 24.60)	4.00 (0 to 12)
Cssmin (ng/mL)	–	352.32 (184.44)
T1/2 (hr)	–	15.69 (5.12)
CL/F (L/hr)	–	17.96 (6.27)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of iSotretinoin and 4- oxo-iSotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of iSotretinoin ranged from 0.46 to 3.65 for pediatric patients.

Indications and Usage for Sotret

Severe Recalcitrant Nodular Acne

Sotret is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Sotret should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Sotret is indicated only for those female patients who are not pregnant, because Sotret can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off iSotretinoin capsules. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

Contraindications

Pregnancy: Category X.

See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

Sotret is contraindicated in patients who are hypersensitive to this medication or to any of its components. Sotret should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).

Warnings

Psychiatric Disorders

Sotret may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of ISotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Sotret therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation maybe necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Sotret and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Sotret therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether Sotret therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of iSotretinoin therapy.

Pseudotumor Cerebri

ISotretinoin capsule use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Sotret immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

Pancreatitis

Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Sotret should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with iSotretinoin capsules. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving iSotretinoin capsules in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of iSotretinoin capsules therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing iSotretinoin capsules.5

Blood lipid determinations should be performed before Sotret is given and then at intervals until the lipid response to Sotret is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Sotret therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Sotret therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with Sotret are unknown.

Animal Studies: In rats given 8 or 32 mg/kg/day of iSotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with iSotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients taking iSotretinoin capsules; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Sotret treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to iSotretinoin capsules therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Sotret, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

ISotretinoin capsules have been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after iSotretinoin capsules treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Sotret immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of Sotret on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with iSotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with iSotretinoin for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second course of iSotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the iSotretinoin population. While causality to Sotret has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Sotret be given at the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Sotret treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of iSotretinoin capsules given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of iSotretinoin capsules. The effect of multiple courses of Sotret on epiphyseal closure is unknown.

Vision Impairment

Visual problems should be carefully monitored. All Sotret patients experiencing visual difficulties should discontinue Sotret treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).

Corneal Opacities

Corneal opacities have occurred in patients receiving iSotretinoin capsules for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with iSotretinoin capsules have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).

Decreased Night Vision

Decreased night vision has been reported during iSotretinoin capsules therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

Precautions

Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive iSotretinoin only from wholesalers registered with iPLEDGE.

iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:

Wholesalers:

For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Sotret, wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of iSotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of iSotretinoin. These include:

• Registering prior to distributing iSotretinoin and reregistering annually thereafter


• Distributing only FDA approved iSotretinoin product


• Only shipping iSotretinoin to
  
  • wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer
  
  
  • pharmacies licensed in the US and registered and activated in the iPLEDGE program
  
  

• Notifying the iSotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order iSotretinoin


• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the iSotretinoin manufacturer (or delegate)


• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not reregister annually


• Providing product flow data to manufacturer (or delegate) as detailed in the wholesalers agreement

Prescribers:

To prescribe iSotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know how to diagnose and treat the various presentations of acne.


• I know the risk and severity of fetal injury/birth defects from iSotretinoin.


• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.


• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer.


• I will comply with the iPLEDGE program requirements described in the booklets entitled The iPLEDGE Program Guide to Best Practices for ISotretinoin and The iPLEDGE Program Prescriber Contraception Counseling Guide.


• Before beginning treatment of female patients of childbearing potential with iSotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after iSotretinoin therapy, unless the patient commits to continuous abstinence.


• I will not prescribe iSotretinoin to any female patient of childbearing potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of iSotretinoin and another pregnancy test 1 month later.


• I will report any pregnancy case that I become aware of while the female patient is on iSotretinoin or 1 month after the last dose to the pregnancy registry.

To prescribe iSotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1. Register each patient in the iPLEDGE program.


2. Confirm monthly that each patient has received counseling and education.


3. For female patients of childbearing potential:
   
   • Enter patient’s two chosen forms of contraception each month.
   
   
   • Enter monthly result from CLIA-certified laboratory conducted pregnancy test.
   
   

ISotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

ISotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to iSotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.


• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial iSotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for iSotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the 2 tests should be at least 19 days.
  
  • For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period and within 7 days of the office visit, immediately preceding the beginning of iSotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.
  
  
  • For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done within 7 days following the office visit, immediately preceding the beginning of iSotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.
  
  

• Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of iSotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.


• Has selected and has committed to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of iSotretinoin therapy, during iSotretinoin therapy, and for 1 month after discontinuing iSotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:

1. Stop taking iSotretinoin immediately, if on therapy


2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse


3. Start using 2 forms of effective contraception simultaneously again for 1 month before resuming iSotretinoin therapy


4. Have a second pregnancy test after using 2 forms of effective contraception for 1 month as described above depending on whether she has regular menses or not.

Effective forms of contraception include both primary and secondary forms of contraception:

Primary forms	Secondary forms
	Barrier forms (always used with spermicide):
• tubal sterilization	• male latex condom
• partner’s vasectomy	• diaphragm
• intrauterine device	• cervical cap
• hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring)	Others:• vaginal sponge (contains spermicide)

Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking iSotretinoin capsules. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use 2 effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Sotret (see PRECAUTIONS: Drug Interactions). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.

If a pregnancy does occur during iSotretinoin treatment, iSotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after iSotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA- 1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

ISotretinoin is contraindicated in female patients who are pregnant. To receive iSotretinoin all patients must meet all of the following conditions:

• Must be registered with the iPLEDGE program by the prescriber


• Must understand that severe birth defects can occur with the use of iSotretinoin by female patients


• Must be reliable in understanding and carrying out instructions


• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with iSotretinoin


• Must fill the prescription within 7 days of the office visit


• Must not donate blood while on iSotretinoin and for 1 month after treatment has ended


• Must not share iSotretinoin with anyone, even someone who has similar symptoms

Female Patients of Childbearing Potential

ISotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing potential must meet the following conditions:

• Must NOT be pregnant or breast-feeding


• Must comply with the required pregnancy testing at a CLIA-certified laboratory


• Must be capable of complying with the mandatory contraceptive measures required for iSotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy


• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after iSotretinoin therapy


• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting iSotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to iSotretinoin


• Must access the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654), before starting iSotretinoin, on a monthly basis during therapy, and 1 month after the last dose to answer questions on the program requirements and to enter the patient’s two chosen forms of contraception


• Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking iSotretinoin or within 1 month of the last dose

Pharmacists:

To dispense iSotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements a

Scot-Tussin

Generic Name: guaifenesin (gwye FEN e sin)

Brand Names: Duratuss G, Ganidin NR, GG 200 NR, GuaiFENesin LA, Liquibid, Muco-Fen 1200, Organidin NR, Q-Bid LA, Robitussin, Scot-Tussin

What is Scot-Tussin (guaifenesin)?

Guaifenesin is an expectorant. It helps loosen congestion in your chest and throat, making it easier to cough out through your mouth.

Guaifenesin is used to reduce chest congestion caused by the common cold, infections, or allergies.

Guaifenesin may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Scot-Tussin (guaifenesin)?

You should not use this medicine if you are allergic to guaifenesin.

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication. This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What should I discuss with my healthcare provider before taking Scot-Tussin (guaifenesin)?

You should not use this medicine if you are allergic to guaifenesin. FDA pregnancy category C. It is not known whether guaifenesin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether guaifenesin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Scot-Tussin (guaifenesin)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication. Take guaifenesin with food if it upsets your stomach.

Measure the liquid form of guaifenesin with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not crush, chew, break, or open a controlled-release, delayed-release, or extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time. Store at room temperature away from moisture, heat, and direct sunlight.

What happens if I miss a dose?

Since cough medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Scot-Tussin (guaifenesin)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Scot-Tussin (guaifenesin) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include:

• 
  

  dizziness or headache,

  
  


• 
  

  a rash, or

  
  


• 
  

  nausea, vomiting, or stomach upset.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect guaifenesin ?

There may be other drugs that can interact with guaifenesin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Scot-Tussin resources

• Scot-Tussin Side Effects (in more detail)
• Scot-Tussin Use in Pregnancy & Breastfeeding
• Scot-Tussin Support Group
• 0 Reviews for Scot-Tussin - Add your own review/rating

• Allfen MedFacts Consumer Leaflet (Wolters Kluwer)


• Allfen Advanced Consumer (Micromedex) - Includes Dosage Information


• Guaifenesin Monograph (AHFS DI)


• Guaifenesin Granules MedFacts Consumer Leaflet (Wolters Kluwer)


• Guaifenesin NR Prescribing Information (FDA)


• Hytuss Immediate-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Mucinex Prescribing Information (FDA)


• Mucinex Sustained-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Mucinex Consumer Overview


• Organidin NR Prescribing Information (FDA)


• Tussin Consumer Overview

Compare Scot-Tussin with other medications

• Bronchitis
• Cough

Where can I get more information?

• Your pharmacist can provide more information about guaifenesin.

See also: Scot-Tussin side effects (in more detail)

Spectracef

Generic Name: cefditoren pivoxil (Oral route)

sef-di-TOE-ren pi-VOX-il

Commonly used brand name(s)

In the U.S.

• Spectracef

Available Dosage Forms:

• Tablet

Therapeutic Class: Antibiotic

Pharmacologic Class: 3rd Generation Cephalosporin

Uses For Spectracef

Cefditoren is used in the treatment of infections caused by bacteria. It works by killing bacteria or preventing their growth.

Cefditoren pivoxil is used to treat some throat and lung infections, including bronchitis and tonsillitis. It is also used to treat some skin infections.

This medicine is available only with your doctor's prescription.

Before Using Spectracef

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of cefditoren in children less than 12 years of age with use in other age groups.

Geriatric

This medicine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Calcium Carbonate


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Famotidine


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate


• Probenecid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Carnitine deficiency—May be worsened by cefditoren

• Kidney disease—Cefditoren may need to be given at a lower dose

Proper Use of Spectracef

To help clear up your infection completely, keep taking this medicine for the full time of treatment, even if you begin to feel better after a few days. Also, if you stop taking this medicine too soon, your symptoms may return.

This medicine works best when there is a constant amount in the blood or urine. To help keep the amount constant, do not miss any doses. Also, it is best to take the doses at evenly spaced times, day and night. For example, if you are to take four doses a day, the doses should be spaced about 6 hours apart. If this interferes with your sleep or other daily activities, or if you need help in planning the best times to take your medicine, check with your health care professional.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Cefditoren should be taken with food to increase absorption of the medicine.

• For oral dosage form (tablets):
  
  • For acute bacterial bronchitis:
    
    • Adults and children 12 years of age and older—400 milligrams (mg) twice a day for ten days.
    
    
    • Children under 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  


• For oral dosage form (tablets):
  
  • For bacterial throat infections or tonsillitis:
    
    • Adults and children 12 years of age and older—200 mg twice a day for ten days.
    
    
    • Children under 12 years of age—Dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Spectracef

If your symptoms do not improve within a few days or if they become worse, check with your doctor.

In some patients, cefditoren may cause diarrhea:

• Severe diarrhea may be a sign of a serious side effect. Do not take any diarrhea medicine without first checking with your doctor . Diarrhea medicines may make your diarrhea worse or make it last longer.


• If you have any questions about this or if mild diarrhea continues or gets worse, check with your health care professional.

Spectracef Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

• Allergic reaction, such as, itching, pain, redness, or swelling of eye or eyelid, watering of eyes, troubled breathing or wheezing, severe skin rash or hives, flushing, headache, fever, chills, runny nose, increased sensitivity to sunlight, joint pain, swollen glands


• leukopenia, such as, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, unusual bleeding or bruising, unusual tiredness, or weakness


• pseudomembranous colitis, such as, abdominal or stomach cramps, pain, bloating, abdominal tenderness, diarrhea, watery and severe, which may also be bloody, fever, increased thirst, nausea or vomiting, unusual tiredness or weakness, or unusual weight loss


• or thrombocythemia, such as, pain, warmth or burning in fingers, toes, and legs, dizziness, problems with vision or hearing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More Common

• Diarrhea


• nausea


• or vaginal moniliasis, such as, thick whitish discharge from the vagina or cervical canal

Less common

• Abdominal pain


• Dyspepsia, such as, acid or sour stomach, belching, heartburn, indigestion, or stomach discomfort, upset or pain


• or headache

Rare

• Abnormal dreams


• anorexia, such as, loss of appetite


• asthenia, such as, lack or loss of strength


• constipation


• dizziness


• dry mouth


• dysgeusia, such as, taste perversion


• eructation, such as, belching, bloated full feeling, excess air or gas in stomach


• fever


• flatulence, such as, passing of gas


• fungal infection


• gastritis, such as, burning feeling in chest or stomach, tenderness in stomach area, stomach upset, or indigestion


• headache


• hyperglycemia, such as, blurred vision, dry mouth, fatigue, flushed, dry skin, fruit-like breath odor, increased hunger, increased thirst, increased urination, loss of consciousness, nausea, stomachache, sweating, troubled breathing, unexplained weight loss, vomiting


• increased appetite


• insomnia, such as, sleeplessness


• leukorrhea, such as, increase in amount of clear vaginal discharge, white vaginal discharge


• mouth ulceration


• myalgia, such as, muscle pain


• nervousness


• oral moniliasis, such as, sore mouth or tongue, white patches in mouth, tongue, or throat


• pain


• peripheral edema, such as, bloating or swelling of face, arms, hands, lower legs, or feet, rapid weight gain, tingling of hands or feet, unusual weight gain or loss


• pharyngitis, such as, body aches or pain, congestion, cough, dryness or soreness of throat, fever, hoarseness, runny nose, tender, swollen glands in neck, trouble in swallowing, or voice changes


• pruritus, such as, itching skin


• rash


• rhinitis, such as, stuffy nose, runny nose, or sneezing


• sinusitis, such as, pain or tenderness around eyes and cheekbones, fever, stuffy or runny nose, headache, cough, shortness of breath or troubled breathing, tightness of chest or wheezing


• somnolence, such as, sleepiness or unusual drowsiness


• stomatitis, such as, swelling or inflammation of the mouth


• sweating


• urinary frequency


• urticaria, such as, hives or welts, itching, redness of skin, or rash


• vaginitis


• vomiting


• or weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Spectracef side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Spectracef resources

• Spectracef Side Effects (in more detail)
• Spectracef Dosage
• Spectracef Use in Pregnancy & Breastfeeding
• Drug Images
• Spectracef Drug Interactions
• Spectracef Support Group
• 3 Reviews for Spectracef - Add your own review/rating

• Spectracef Prescribing Information (FDA)


• Spectracef Concise Consumer Information (Cerner Multum)


• Spectracef Monograph (AHFS DI)


• Spectracef MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Spectracef with other medications

• Bronchitis
• Pneumonia
• Skin and Structure Infection
• Skin Infection
• Tonsillitis/Pharyngitis

Selzentry

maraviroc

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

 Hepatotoxicity has been reported with use of Selzentry. Severe rash or evidence of a systemic allergic reaction (e.g., fever, eosinophilia, or elevated IgE) prior to the development of hepatotoxicity may occur. Patients with signs or symptoms of hepatitis or allergic reaction following use of Selzentry should be evaluated immediately [see Warnings and Precautions (5.1)].

Indications and Usage for Selzentry

Selzentry, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1.

This indication is based on analyses of plasma HIV-1 RNA levels in 2 controlled studies of Selzentry in treatment-experienced subjects and one study in treatment-naive subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral-experienced (nucleoside reverse transcriptase inhibitor [NRTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], protease inhibitor [PI], or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with Selzentry:

• Adult patients infected with only CCR5-tropic HIV-1 should use Selzentry.


• Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for use of Selzentry. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on Selzentry [see Microbiology (12.4), Clinical Studies (14.3)].


• Use of Selzentry is not recommended in subjects with dual/mixed- or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a Phase 2 study of this patient group.


• The safety and efficacy of Selzentry have not been established in pediatric patients.


• In treatment-naive subjects, more subjects treated with Selzentry experienced virologic failure and developed lamivudine resistance compared with efavirenz [see Microbiology (12.4), Clinical Studies (14.3)].

Selzentry Dosage and Administration

Dose Recommendations for Patients With Normal Renal Function

The recommended dose of Selzentry differs based on concomitant medications due to drug interactions (see Table 1). Selzentry can be taken with or without food. Selzentry must be given in combination with other antiretroviral medications.

Table 1 gives the recommended dose adjustments [see Drug Interactions (7.1)].

Table 1. Recommended Dosing Regimen

Concomitant Medications	Dose of Selzentry
Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including: protease inhibitors (except tipranavir/ritonavir) delavirdine ketoconazole, itraconazole, clarithromycin other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)	150 mg twice daily
Other concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide	300 mg twice daily
Potent CYP3A inducers (without a potent CYP3A inhibitor) including: efavirenz rifampin etravirine carbamazepine, phenobarbital, and phenytoin	600 mg twice daily

Dose Recommendations for Patients With Renal Impairment

Table 2 provides dosing recommendations for patients based on renal function and concomitant medications.

Table 2. Recommended Dosing Regimens Based on Renal Function

Concomitant Medicationsa	Dose of Selzentry Based on Renal Function
	Normal (CrCl>80 mL/min)	Mild (CrCl >50 and ≤80 mL/min)	Moderate (CrCl ≥30 and ≤50 mL/min)	Severe (CrCl <30 mL/min)	End-Stage Renal Disease (ESRD) On Regular Hemodialysis
Potent CYP3A inhibitors (with or without a CYP3A inducer)a	150 mg twice daily	150 mg twice daily	150 mg twice daily	NR	NR
Other concomitant medicationsa	300 mg twice daily	300 mg twice daily	300 mg twice daily	300 mg twice dailyb	300 mg twice dailyb
Potent CYP3A Inducers (without a potent CYP3A inhibitor)a	600 mg twice daily	600 mg twice daily	600 mg twice daily	NR	NR

NR = Not recommended.

a See Table 1 for the list of concomitant medications.

b The dose of Selzentry should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension [see Warnings and Precautions (5.2)].

Dosage Forms and Strengths

• 150-mg blue, oval, film-coated tablets debossed with “MVC 150” on one side and plain on the other.


• 300-mg blue, oval, film-coated tablets debossed with “MVC 300” on one side and plain on the other.

Contraindications

Selzentry should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl <30 mL/min) who are taking potent CYP3A inhibitors or inducers.

Warnings and Precautions

Hepatotoxicity

  Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.

  Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with Selzentry and at other time points during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. Discontinuation of Selzentry should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

  Caution should be used when administering Selzentry to patients with pre-existing liver dysfunction or who are coinfected with viral hepatitis B or C. The safety and efficacy of Selzentry have not been specifically studied in patients with significant underlying liver disorders. In studies of treatment-experienced HIV-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with administration of Selzentry.

Cardiovascular Events

Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received Selzentry had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies in treatment-experienced studies (total exposure 609 patient-years [300 on Selzentry once daily + 309 on Selzentry twice daily]), while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to use of Selzentry, and the relative contribution of Selzentry to these events is not known.

In the Phase 2b/3 study in treatment-naive subjects, 3 subjects (0.8%) who received Selzentry had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for Selzentry and efavirenz, respectively).

When Selzentry was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when Selzentry was given at the recommended dose in HIV subjects in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering Selzentry in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure.

Postural Hypotension in Patients With Renal Impairment: Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients. Selzentry should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of Selzentry in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.2)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii, Mycobacterium tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.

Potential Risk of Infection

Selzentry antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups during the Phase 3 treatment-experienced studies of Selzentry. While there was a higher rate of certain upper respiratory tract infections reported in the arm receiving Selzentry compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% vs 5%) reported in subjects receiving Selzentry. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the arm receiving Selzentry when adjusted for exposure compared with placebo (8 per 100 patient-years).

In the Phase 2b/3 study in treatment-naive subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for Selzentry compared with 2.4 for efavirenz per 100 patient-years of exposure.

Patients should be monitored closely for evidence of infections while receiving Selzentry.

Potential Risk of Malignancy

While no increase in malignancy has been observed with Selzentry, due to this drug’s mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.

The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment-experienced studies was 4.6 for Selzentry compared with 9.3 on placebo. In treatment-naive subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for Selzentry and efavirenz, respectively.

Long-term follow-up is needed to more fully assess this risk.

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]


• Cardiovascular events [see Warnings and Precautions (5.2)]

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Studies in Treatment-Experienced Subjects: The safety profile of Selzentry is primarily based on 840 HIV-infected subjects who received at least 1 dose of Selzentry during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.

Assessment of treatment-emergent adverse events is based on the pooled data from 2 studies in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with Selzentry for subjects in these studies was 48 weeks, with the total exposure on Selzentry twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.

The most common adverse events reported with twice-daily therapy with Selzentry with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. Additional adverse events that occurred with once-daily dosing at a higher rate than both placebo and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these 2 studies, the rate of discontinuation due to adverse events was 5% for subjects who received Selzentry twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of Selzentry.

The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving Selzentry twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on Selzentry compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both Selzentry twice daily and placebo.

Dizziness or postural dizziness occurred in 8% of subjects on either Selzentry or placebo, with 2 subjects (0.5%) on Selzentry permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.

Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 3. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with Selzentry are included; events that occurred at the same or higher rate on placebo are not displayed.

Table 3. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality)(≥2% on Selzentry and at a higher rate compared with placebo) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

	Selzentry Twice Dailya		Placebo
	N = 426 (%)	Exposure-adjusted rate (per 100 pt-yrs) PYE = 309b	N = 426 (%)	Exposure-adjusted rate (per 100 pt-yrs) PYE = 111b
Eye Disorders
Conjunctivitis	2	3	1	3
Ocular infections, inflammations, and associated manifestations	2	3	1	2
Gastrointestinal Disorders
Constipation	6	9	3	6
General Disorders and Administration Site Conditions
Pyrexia	13	20	9	17
Pain and discomfort	4	5	3	5
Infections and Infestations
Upper respiratory tract infection	23	37	13	27
Herpes infection	8	11	4	8
Sinusitis	7	10	3	6
Bronchitis	7	9	5	9
Folliculitis	4	5	2	4
Pneumonia	2	3	5	10
Anogenital warts	2	3	1	3
Influenza	2	3	0.5	1
Otitis media	2	3	0.5	1
Metabolism and Nutrition Disorders
Appetite disorders	8	11	7	13
Musculoskeletal and Connective Tissue Disorders
Joint-related signs and symptoms	7	10	3	5
Muscle pains	3	4	0.5	1
Neoplasms Benign, Malignant, and Unspecified
Skin neoplasms benign	3	4	1	3
Nervous System Disorders
Dizziness/postural dizziness	9	13	8	17
Paresthesias and dysesthesias	5	7	3	6
Sensory abnormalities	4	6	1	3
Disturbances in consciousness	4	5	3	6
Peripheral neuropathies	4	5	3	6
Psychiatric Disorders
Disturbances in initiating and maintaining sleep	8	11	5	10
Depressive disorders	4	6	3	5
Anxiety symptoms	4	5	3	7
Renal and Urinary Disorders
Bladder and urethral symptoms	5	7	1	3
Urinary tract signs and symptoms	3	4	1	3
Respiratory, Thoracic, and Mediastinal Disorders
Coughing and associated symptoms	14	21	5	10
Upper respiratory tract signs and symptoms	6	9	3	6
Nasal congestion and inflammations	4	6	3	5
Breathing abnormalities	4	5	2	5
Paranasal sinus disorders	3	4	0.5	1
Skin and Subcutaneous Tissue Disorders
Rash	11	16	5	11
Apocrine and eccrine gland disorders	5	7	4	7.5
Pruritus	4	5	2	4
Lipodystrophies	3	5	0.5	1
Erythemas	2	3	1	2
Vascular Disorders
Vascular hypertensive disorders	3	4	2	4

a300-mg dose equivalent. 

bPYE = Patient-years of exposure.

Laboratory Abnormalities: Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in >2% of subjects receiving Selzentry.

Table 4. Maximum Shift in Laboratory Test Values (Without Regard to Baseline)

Incidence ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Laboratory Parameter Preferred Term	Limit	Selzentry Twice Daily + OBT (N = 421)a %	Placebo + OBT (N = 207)a %
Aspartate aminotransferase	>5.0x ULN	4.8	2.9
Alanine aminotransferase	>5.0x ULN	2.6	3.4
Total bilirubin	>5.0x ULN	5.5	5.3
Amylase	>2.0x ULN	5.7	5.8
Lipase	>2.0x ULN	4.9	6.3
Absolute neutrophil count	<750/mm3	4.3	2.4

aPercentages based on total subjects evaluated for each laboratory parameter.

Study in Treatment-Naive Subjects:Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Study A4001026, a double-blind, comparative, controlled study in which 721 treatment-naive subjects received Selzentry 300 mg twice daily (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 5. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with Selzentry are included; events that occurred at the same or higher rate on efavirenz are not displayed.

Table 5. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality) (≥2% on Selzentry and at a higher rate compared with efavirenz) Study A4001026 (96 Weeks)

	Selzentry 300 mg Twice Daily + Zidovudine/Lamivudine (N = 360) %	Efavirenz 600 mg Once Daily + Zidovudine/Lamivudine (N = 361) %
Blood and Lymphatic System Disorders
Anemias NEC	8	5
Neutropenias	4	3
Ear and Labyrinth Disorders
Ear disorders NEC	3	2
Gastrointestinal Disorders
Flatulence, bloating, and distention	10	7
Gastrointestinal atonic and hypomotility disorders NEC	9	5
Gastrointestinal signs and symptoms NEC	3	2
General Disorders and Administration Site Conditions
Body temperature perception	3	1
Infections and Infestations
Bronchitis	13	9
Herpes infection	7	6
Upper respiratory tract infection	32	30
Bacterial infections NEC	6	3
Herpes zoster/varicella	5	4
Lower respiratory tract and lung infections	3	2
Neisseria infections	3	0
Tinea infections	4	3
Viral infections NEC	3	2
Musculoskeletal and Connective Tissue Disorders
Joint-related signs and symptoms	6	5
Nervous System Disorders
Memory loss (excluding dementia)	3	1
Paresthesias and dysesthesias	4	3
Renal and Urinary Disorders
Bladder and urethral symptoms	4	3
Reproductive System and Breast Disorders
Erection and ejaculation conditions and disorders	3	2
Respiratory, Thoracic, and Mediastinal Disorders
Upper respiratory tract signs and symptoms	9	5
Skin and Subcutaneous Disorders
Acnes	3	2
Alopecias	2	1
Lipodystrophies	4	3
Nail and nail bed conditions (excluding infections and infestations)	6	2