Package/Label Display Panel – Blister– 100 mg

Ritonavir
Tablet USP

100 mg

**WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR

LIFE THREATENING REACTIONS**

1 INDICATIONS AND USAGE

Ritonavir tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

4 CONTRAINDICATIONS

• When co-administering ritonavir tablets with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
• Ritonavir tablets are contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
• Ritonavir tablets are contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
• Alpha 1- Adrenoreceptor Antagonist: alfuzosin
• Antianginal: ranolazine
• Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine
• Antifungal: voriconazole
• Anti-gout: colchicine
• Antipsychotics: lurasidone, pimozide
• Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
• GI Motility Agent: cisapride
• HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
• Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
• PDE5 Inhibitor: sildenafil (Revatio ®) when used for the treatment of pulmonary arterial hypertension
• Sedative/Hypnotics: triazolam, orally administered midazolam
• Ritonavir tablets are contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
• Anticancer Agents: apalutamide
• Herbal Products: St. John’s Wort (hypericum perforatum)

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Drug Interactions [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.4)]
• Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.5)]

When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

Adverse Reactions in Adults
The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 2 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined Phase II/IV studies.

The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

Laboratory Abnormalities in Adults
Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities.

Adverse Reactions in Pediatric Patients
Ritonavir has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.

Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in ritonavir clinical trials.

Laboratory Abnormalities in Pediatric Patients
The following Grade 3 to 4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).

6.2 Postmarketing Experience

The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of ritonavir. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to ritonavir exposure.

Body as a Whole
Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.

Cardiovascular System
First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see Warnings and Precautions (5.6)]

Cardiac and neurologic events have been reported when ritonavir has been co- administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.

Endocrine System
Cushing’s syndrome and adrenal suppression have been reported when ritonavir has been co‑administered with fluticasone propionate or budesonide.

Nervous System
There have been postmarketing reports of seizure. Also, see Cardiovascular System.

Renal and Urinary Disorders
Nephrolithiasis

Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis (TEN) has been reported.

7 DRUG INTERACTIONS

When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

7.1 Potential for Ritonavir to Affect Other Drugs

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co- administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 4.

Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

7.2 Established and Other Potentially Significant Drug Interactions

Table 4 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] for magnitude of interaction.

Patient Information

8442025/1123F

Ritonavir Tablets USP
(ri toe' na vir)

What is the most important information I should know about ritonavir tablets?

• Ritonavir tablets can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with ritonavir tablets. See the section “Who should not take ritonavir tablets?”

What are ritonavir tablets?

• Ritonavir tablets are prescription medicines that are used with other antiviral medicines to treat people with human immunodeficiency virus (HIV-1) infection.

HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

Do not take ritonavir tablets if you or your child:

• are allergic to ritonavir or any of the ingredients in ritonavir tablets. See the end of this leaflet for a complete list of ingredients in ritonavir tablets.
• If you take any of the following medicines:
  • alfuzosin
  • apalutamide
  • ranolazine
  • dronedarone
  • colchicine, if you have kidney or liver problems.
  • lurasidone
  • pimozide
  • amiodarone
  • ergot-containing medicines, including:
    • dihydroergotamine mesylate
    • ergotamine tartrate
    • methylergonovine maleate
  • cisapride
  • flecainide
  • lovastatin
  • simvastatin
  • lomitapide
  • sildenafil (REVATIO ®) only when used for treating the lung problem, pulmonary arterial hypertension (PAH)
  • triazolam
  • midazolam when taken by mouth
  • propafenone
  • quinidine
  • St. John’s Wort (Hypericum perforatum) or a product that contains St. John’s wort
  • voriconazole if your ritonavir tablets dose is 400 mg every 12 hours or greater

Serious problems can happen if you or your child takes any of these medicines with ritonavir tablets.

Before taking ritonavir tablets, tell your healthcare provider about all of your medical conditions, including if you or your child:

• have liver problems, including Hepatitis B or Hepatitis C
• have heart problems
• have high blood sugar (diabetes)
• have bleeding problems or hemophilia
• are pregnant or plan to become pregnant.
  • Ritonavir oral solution contains alcohol. You should not take ritonavir oral solution during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with ritonavir tablets.
  • Ritonavir tablets may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with ritonavir tablets. *Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
• are breastfeeding or plan to breastfeed.Do not breastfeed if you take ritonavir tablets.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Ritonavir may pass into your breastmilk.
  • Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with ritonavir tablets.Keep a list of your medicines to show your healthcare provider and pharmacist.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with ritonavir tablets.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ritonavir tablets with other medicines.

How should I take ritonavir tablets?

• Take ritonavir tablets exactly as your healthcare provider tells you to take it.
• You should stay under a healthcare provider's care during treatment with ritonavir tablets. Do not change your dose of ritonavir tablets or stop your treatment without talking with your healthcare provider first.
• If your child is taking ritonavir tablets, your child’s healthcare provider will decide the right dose based on your child's height and weight. Tell your healthcare provider if your child’s weight changes. If your child does not tolerate ritonavir oral solution or ritonavir oral powder, ask your child’s healthcare provider for advice.
• Swallow ritonavir tablets whole. Do not chew, break, or crush tablets before swallowing. If you cannot swallow ritonavir tablets whole, tell your healthcare provider. You may need a different medicine.
• Take ritonavir tablets with meals.
• Do not run out of ritonavir tablets. Get your ritonavir tablets prescription refilled from your healthcare provider or pharmacy before you run out.
• If you miss a dose of ritonavir tablets, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, wait and take the next dose at the regular time. Do not double the next dose.
• If you take too much ritonavir tablets, call your local poison control center or go to the nearest hospital emergency room right away.

What are the possible side effects of ritonavir tablets?
Ritonavir tablets can cause serious side effects including:

• See**“What is the most important information I should know about ritonavir tablets?”** *Liver problems. Some people taking ritonavir tablets in combination with other antiviral medicines have developed liver problems which may be life-threatening. Your healthcare provider should do regular blood tests during your combination treatment with ritonavir tablets. If you have chronic hepatitis B or C infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider right away if you get any of the following signs and symptoms of liver problems:
• loss of appetite
• yellowing of your skin or whites of your eyes
• pain or tenderness on your right side below your ribs
• itchy skin *Inflammation of your pancreas (pancreatitis). Ritonavir tablets can cause serious pancreas problems, which may lead to death. Tell your healthcare provider right away if you have signs or symptoms of pancreatitis such as:
• nausea
• vomiting
• stomach (abdomen) pain *Allergic reactions. Sometimes these allergic reactions can become severe and require treatment in a hospital. Call your healthcare provider right away if you develop a rash. Stop taking ritonavir tablets and get medical help right away if you have any of the following symptoms of a severe allergic reaction:
• trouble breathing
• sweating
• wheezing
• swelling of your face, lips or tongue
• dizziness or fainting
• muscle or joint pain
• throat tightness or hoarseness
• blisters or skin lesions
• fast heartbeat or pounding in your chest (tachycardia)
• mouth sores or ulcers *Changes in the electrical activity of your heart called PR prolongation. PR prolongation can cause irregular heartbeats. Tell your healthcare provider right away if you have symptoms such as:
• dizziness
• feel faint or pass out
• lightheadedness
• abnormal heart beat *Increase in cholesterol and triglyceride levels. Treatment with ritonavir tablets may increase your blood levels of cholesterol and triglycerides. Your healthcare provider should do blood tests before you start your treatment with ritonavir tablets and regularly to check for an increase in your cholesterol and triglycerides levels. *Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including ritonavir tablets can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often during treatment with ritonavir tablets. *Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. *Change in body fat can happen in some people who taking HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. *Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including ritonavir tablets. *Kidney stones

The most common side effects of ritonavir tablets include:

• diarrhea
• tingling feeling or numbness in hands or feet or around the lips
• nausea
• vomiting
• rash
• upper and lower stomach (abdominal) pain
• feeling weak or tired

Ritonavir oral solution contains a large amount of alcohol. If a toddler or young child accidentally drinks more than the recommended dose of ritonavir oral solution, it could make him/her sick from too much alcohol. Go to the nearest emergency room right away if this happens.

These are not all of the possible side effects of ritonavir tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ritonavir tablets?

• Use ritonavir tablets by the expiration date.
• Store at or below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted.
• Exposure to high humidity outside the blister for longer than 2 weeks is not recommended.

Keep ritonavir tablets and all medicines out of the reach of children.

General information about the safe and effective use of ritonavir tablets
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use ritonavir tablets for a condition for which it was not prescribed. Do not give ritonavir tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ritonavir tablets that is written for healthcare professionals.

What are the ingredients in ritonavir tablets?
Active ingredient: ritonavir
Inactive ingredients: copovidone, corn starch, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, hypromellose, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate, powdered cellulose, silicified microcrystalline cellulose, sodium stearyl fumarate, sorbitan monolaurate, talc, and titanium dioxide.

For more information about the drug product, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.
For more information about the packaging or labeling, call American Health Packaging at 1-800-707-4621.

The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. The makers of these brands are not affiliated with and do not endorse Aurobindo Pharma Limited or its products.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Dispense with Patient Information
To order more Patient Information Leaflets call American Health Packaging at 1-800-707-4621.

Distributed by:
American Health Packaging
Columbus, OH 43217

8442025/1123F

15 REFERENCES

1. Sewester CS. Calculations. In: Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Co; January, 1997:xix.

2 DOSAGE AND ADMINISTRATION

2.1 General Administration Recommendations

• Ritonavir tablets must be used in combination with other antiretroviral agents.
• Ritonavir tablets are administered orally. Ritonavir tablets should be swallowed whole, and not chewed, broken or crushed. Take ritonavir tablets with meals.

General Dosing Guidelines
Patients who take the 600 mg twice daily soft gel capsule ritonavir dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (C max) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3)]. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

2.3 Dosage Recommendations in Adults

Recommended Dosage for Treatment of HIV-1:
The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment- emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir tablets should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration [see Dosage and Administration (2.6)].

Pregnant Women
Ritonavir oral solution is not recommended during pregnancy due to its ethanol content. Ritonavir oral solution contains the excipients ethanol and propylene glycol [see Use in Specific Populations (8.1)].

2.4 Dosage Recommendations in Pediatric Patients

Ritonavir tablets must be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of ritonavir tablets in pediatric patients older than 1 month is 350 to 400 mg per m 2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir tablets should be started at 250 mg per m 2 twice daily and increased at 2 to 3 day intervals by 50 mg per m 2 twice daily. If patients do not tolerate 400 mg per m 2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered [see Dosage and Administration (2.6)].

Pediatric Dosage Guidelines for Oral Solution
Ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2)].

Ritonavir oral solution contains the excipients ethanol and propylene glycol. Special attention should be given to accurate calculation of the dose of ritonavir oral solution, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 1 to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)]. When possible, dose should be administered using a calibrated dosing syringe.

Body surface area (BSA) can be calculated as follows 1:

Pediatric Dosage Guidelines for Oral Powder
Ritonavir oral powder should be used only for dosing increments of 100 mg. Ritonavir powder should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. Ritonavir oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals.

2.6 Dose Modification due to Drug Interaction

Dose reduction of ritonavir tablet is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5.1), and Drug Interactions (7)].

3 DOSAGE FORMS AND STRENGTHS

Ritonavir tablets USP, 100 mg are white to off-white, film-coated, ovaloid tablets, debossed with ‘Z’ on one side and ‘24’ on other side.

8 USE IN SPECIFIC POPULATIONS

When co-administering ritonavir with other protease inhibitors, see the full prescribing information for the co-administered protease inhibitor including important information for use in special populations.

8.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ritonavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary
Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data].

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor [see Data].

Ritonavir oral solution is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Clinical Considerations, Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

The 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 to 4% and 15 to 20%, respectively.

Clinical Considerations
Dose Adjustments During Pregnancy and the Postpartum Period
Ritonavir oral solution contains ethanol and propylene glycol and is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

Data
Human Data
Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 2.9%) following first- trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3% to 3.5%) following second and third trimester exposure to ritonavir-containing regimens.

While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data
Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day 20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on a body surface area conversion factor.

8.2 Lactation

Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Limited published data reports that ritonavir is present in human milk.

There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ritonavir.

8.3 Females and Males of Reproductive Potential

Contraception
Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2)].

8.4 Pediatric Use

In HIV-infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

8.5 Geriatric Use

Clinical studies of ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Acute Overdosage - Human Overdose Experience
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg per day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post- marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

Management of Overdosage
Ritonavir oral solution contains ethanol and propylene glycol. Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal.

Treatment of overdose with ritonavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with ritonavir. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with ritonavir oral solution. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with ritonavir.

11 DESCRIPTION

Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1‑methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C 37H 48N 6O 5S 2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Ritonavir USP is a white to light-tan, crystalline powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Ritonavir tablets USP are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: copovidone, corn starch, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, hypromellose, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate, powdered cellulose, silicified microcrystalline cellulose, sodium stearyl fumarate, sorbitan monolaurate, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ritonavir is an antiretroviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.6)].

12.3 Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD 4 greater than or equal to 50 cells per μL). See Table 5 for ritonavir pharmacokinetic characteristics.

Absorption
The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.

Ritonavir tablets are not bioequivalent to ritonavir capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC (0- ∞) met equivalence criteria but mean C max was increased by 26% (92.8% confidence intervals: ↑15 to ↑39%).

No information is available comparing ritonavir tablets to ritonavir capsules under fasting conditions.

After administration of a single 100 mg dose under fed conditions (617 Kcal, 29% calories from fat), ritonavir oral powder demonstrated comparable bioavailability to the oral solution.

Effect of Food on Oral Absorption
The bioavailability of ritonavir tablet, oral solution, and oral powder is decreased under fed conditions as compared to fasted conditions.

Following the administration of a 100 mg tablet dose of ritonavir, C max and AUC inf of ritonavir were decreased by 21 to 23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Following the administration of a 600 mg dose ritonavir oral solution, C max and AUC inf of ritonavir were decreased by 23% and 7%, respectively, under nonfasting conditions (514 Kcal, 10% from fat) relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera ® or Ensure ® did not significantly affect the extent and rate of ritonavir absorption.

Following the administration of a 100 mg dose of ritonavir oral powder, C max and AUC inf of ritonavir were decreased by 23 to 49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Metabolism
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.

Elimination
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Special Populations
Gender, Race and Age
No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.

Pediatric Patients
Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m 2 twice-daily to 400 mg per m 2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m 2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m 2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m 2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m 2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m 2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m 2 twice-daily compared to the 350 mg per m 2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m 2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.

Renal Impairment
Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic Impairment
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.

Pregnancy
Based on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.

Drug Interactions
[see also Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]

Table 6 and Table 7 summarize the effects on AUC and C max, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 4 in Drug Interactions (7).

ND=not determined

Parallel group design; entries are subjects receiving combination and control regimens, respectively.

90% CI presented for simeprevir (change in exposure presented as percentage increase)

Sulfamethoxazole and trimethoprim taken as single combination tablet.

90% CI presented for R- and S-warfarin AUC and Cmax ratios.

12.4 Microbiology

Mechanism of Action
Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the Gag-Pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

Antiviral Activity in Cell Culture
The activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC 50) value of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC 50 value for low passage clinical isolates was 22 nM (n = 13). In MT 4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that greater than 20 microM was required to inhibit cellular growth by 50% resulting in a cell culture therapeutic index of at least 1000.

Resistance
HIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene leading to amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n = 18) and genotypic (n = 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Substitutions associated with the HIV–1 viral protease in isolates obtained from 43 patients appeared to occur in a stepwise and ordered fashion at positions V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional 5 specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a greater than or equal to 5-fold decrease in viral sensitivity in cell culture from baseline.

Cross-Resistance to Other Antiretrovirals
Among protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in cell culture but did not demonstrate a concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from 5 patients were also tested for cross- resistance to amprenavir and nelfinavir; isolates from 3 patients had a decrease in susceptibility to nelfinavir (6- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One zidovudine-resistant HIV-1 isolate tested in cell culture retained full susceptibility to ritonavir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis
However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility
Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

14 CLINICAL STUDIES

The activity of ritonavir as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

14.1 Advanced Patients with Prior Antiretroviral Therapy

Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD 4 cell counts less than or equal to 100 cells per μL. Ritonavir 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1,090 patients, with mean baseline CD 4 cell count at study entry of 32 cells per μL. After the clinical benefit of ritonavir therapy was demonstrated, all patients were eligible to switch to open-label ritonavir for the duration of the follow-up period. Median duration of double-blind therapy with ritonavir and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to ritonavir and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to ritonavir compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant.

Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to ritonavir compared to 26% (142/547) for patients initially randomized to placebo. This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to ritonavir therapy, the survival benefit of ritonavir cannot be precisely estimated.

During the double-blind phase of Study 247, CD 4 cell counts increases from baseline for patients randomized to ritonavir at Week 2 and Week 4 were observed. From Week 4 and through Week 24, mean CD 4 cell counts for patients randomized to ritonavir appeared to plateau. In contrast, there was no apparent change in mean CD 4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

14.2 Patients without Prior Antiretroviral Therapy

In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD 4 = 364 cells per μL) were randomized to receive either ritonavir 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.

During the double-blind phase of study 245, greater mean CD 4 cell count increases were observed from baseline to Week 12 in the ritonavir-containing arms compared to the zidovudine arms. Mean CD 4 cell count changes subsequently appeared to plateau through Week 24 in the ritonavir arm, whereas mean CD 4 cell counts gradually diminished through Week 24 in the zidovudine and ritonavir plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the ritonavir-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the ritonavir and zidovudine arms or gradually rebounded toward baseline in the ritonavir plus zidovudine arm.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ritonavir Tablets USP, 100 mg are white to off-white, film-coated, ovaloid tablets, debossed with ‘Z’ on one side and ‘24’ on other side.
Unit dose packages of 30 (5 x 6) NDC 60687-420-25

Recommended Storage
Store at or below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted. For patient use: exposure of this product to high humidity outside the blister for longer than 2 weeks is not recommended.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

General Administration Information [seeDosage and Administration (2)]:

• Advise patients and caregivers to pay special attention to accurate preparation and administration of their dose to minimize the risk of accidental overdose or underdose of ritonavir.
• Advise caregivers to inform their healthcare provider if their child’s weight changes in order to make sure that the child’s ritonavir dose is adjusted as needed.
• Advise patients to take ritonavir with meals.
• For adult patients taking ritonavir tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.
• Advise patients to remain under the care of a physician while using ritonavir and to take ritonavir and other concomitant antiretroviral therapy every day as prescribed. Ritonavir must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of ritonavir is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
• Continued ritonavir therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.
• Ritonavir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ritonavir.

Drug Interactions

• Ritonavir may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort.
• Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with ritonavir because hormonal levels may decrease [see Drug Interactions (7.2), Use in Specific Populations (8.3)].

Hepatotoxicity
Pre-existing liver disease including Hepatitis B or C can worsen with use of ritonavir. This can be seen as worsening of transaminase elevations or hepatic decompensation. Advise patients that their liver function tests will need to be monitored closely especially during the first several months of ritonavir treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin [see Warnings and Precautions (5.3)].

Pancreatitis
Pancreatitis, including some fatalities, has been observed in patients receiving ritonavir therapy. Advise patients to notify their healthcare provider of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis [see Warnings and Precautions (5.4)].

Allergic Reactions/Hypersensitivity
Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving ritonavir. Advise patients to contact their healthcare provider if they develop a rash while taking ritonavir [see Warnings and Precautions (5.5)].

PR Interval Prolongation
Ritonavir may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness [see Warnings and Precautions (5.6)].

Lipid Disorders
Advise patients that treatment with ritonavir therapy can result in substantial increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions (5.7)].

Diabetes Mellitus/Hyperglycemia
Advise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported and to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on ritonavir as they may require a change in their diabetes treatment or new treatment [see Warnings and Precautions (5.8)].

Immune Reconstitution Syndrome
Advise patients that immune reconstitution syndrome has been reported in HIV- infected patients treated with combination antiretroviral therapy, including ritonavir [see Warnings and Precautions (5.9)].

Fat Redistribution
Advise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10)].

Patients with Hemophilia
Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as ritonavir [see Warnings and Precautions (5.11)].

Ritonavir Oral Solution Not Recommended During Pregnancy
Advise pregnant women that use of ritonavir oral solution during pregnancy is not recommended due to its ethanol content [see Dosage and Administration (2.3) and Use in Specific Population (8.1)].

Pregnancy Exposure Registry
Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to ritonavir [see Use in Specific Populations (8.1)].

Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Dispense with Patient Information
To order more Patient Information Leaflets call American Health Packaging at 1-800-707-4621.

PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Aurobindo Pharma USA, Inc. as follows:
(100 mg / 30 UD) NDC 60687-420-25 packaged from NDC 65862-687

Distributed by:
American Health Packaging
Columbus, OH 43217

8442025/1123F