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Product
Antiretroviral products (Ritomune)
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Antiretroviral products (Ritomune)
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Ritomune
Ritonavir Tablets
COMPOSITION
Each tablet contains
Ritonavir ……..100 mg
DESCRIPTION
RITOMUNE is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).
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PHARMACOLOGY
Pharmacodynamics
Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. 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.
Pharmacokinetics
The pharmacokinetics of ritonavir has been studied in healthy volunteers and HIV-infected patients (CD4 ≥ 50 cells/ m L).
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 conditions, respectively. The peak plasma concentration of ritonvir (C max ) after a single dose of 600 mg is 11.2 ± 3.6 m g/ml. Percentage of ritonavir bound to plasma proteins is 98 to 99%.
Effect of Food on Absorption: After a single 600 mg dose under non-fasting conditions, the soft gelatin capsule formulation yielded a mean ± SD area under the plasma concentration-time curve (AUC) of 121.7 ± 53.8 µg•h/mL. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal.
Metabolism: Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14 C-ritonavir oral solution (n=5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. 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 (isopropylthiazole oxidation metabolite).
Elimination: In a study of five subjects receiving a 600 mg dose of 14 C-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. Also, 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. The half-life of ritonavir is 3-5 hours.
INDICATIONS
RITOMUNE is indicated in combination with other antiretroviral agents for the treatment of HIV-infection.
DOSAGE AND ADMINISTRATION
It is recommended that RITOMUNE be taken with meals if possible. RITOMUNE is administered orally.
Adults
Recommended dosage: The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.
Concomitant therapy: If saquinavir and ritonavir are used in combination, the dosage of saquinavir should be reduced to 400 mg twice daily. The optimum dosage of ritonavir (400 mg or 600 mg twice daily), in combination with saquinavir, has not been determined; however, the combination regimen was better tolerated in patients who received ritonavir 400 mg twice daily.
General Dosing Guidelines
Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paresthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with RITOMUNE and reverse transcriptase inhibitors may improve gastrointestinal tolerance by initiating RITOMUNE alone and subsequently adding reverse transcriptase inhibitors before completing two weeks of RITOMUNE monotherapy.
CONTRAINDICATIONS
RITOMUNE is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.
RITOMUNE should not be administered concurrently with the drugs listed in Table 1 because competition, for primarily CYP3A, by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.
Table 1: Drugs that are Contraindicated with Ritonavir Use
| Drug Class |
Drugs Within Class that are Contraindicated with Ritonavir |
| Antiarrhythmics |
Amiodarone, bepridil, flecainide, propafenone, quinidine
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| Antihistamines |
Astemizole, terfenadine |
| Ergot derivatives |
Dihydroergotamine, ergotamine, ergonovine, methlylergonovine |
| Sedative/hypnotics |
Midazolam, triazolam |
| GI motility agent |
Cisapride |
| Neuroleptic |
Pimozide |
WARNINGS AND PRECAUTIONS
ALERT: Find out about medicines that should NOT be taken with RITOMUNE .
Allergic Reactions
Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome have also been reported.
Hepatic Reactions
Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs. There may be an increased risk for transaminases elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of ritonavir treatment.
There have been post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.
Pancreatitis
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.
Diabetes Mellitus/Hyperglycaemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
General
Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function (see Hepatic Reactions ).
Resistance/Cross-Resistance
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.
Haemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and haemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Lipid Disorders
Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See Tables 2 and 4 for additional information on potential drug interactions with ritonavir and HMG CoA reductase inhibitors.
Laboratory Tests
Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with reverse transcriptase inhibitors, physicians should refer to the complete product information for each of these drugs.
Drug Interactions
Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro , but to a lesser extent than CYP3A. Co-administration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects. (see CONTRAINDICATIONS – Table 1 Drugs That Are Contraindicated with ritonavir, WARNINGS and PRECAUTIONS – Table 2 Drugs That Should Not Be Co-administered with ritonavir, Table 3 Established Drug Interactions and Tables 4 and 5 Predicted Drug Interactions: Use with Caution) .
The magnitude of the interactions and therapeutic consequences between ritonavir and the drugs listed in Tables 4 and 5 Predicted Drug Interactions: Use With Caution cannot be predicted with any certainty. When co-administering ritonavir with any agent listed in Tables 4 and 5 Predicted Drug Interactions: Use With Caution, special attention is warranted. Refer to WARNINGS and PRECAUTIONS: Table 3 Established Drug Interactions and Tables 4 and 5:Predicted Drug Interactions for additional information.
Cardiac and neurologic events have been reported with ritonavir when co-administered with disopyramide, mexiletine, nefazodone, fluoxetine and beta-blockers. The possibility of drug interaction cannot be excluded.
Particular caution should be used when prescribing sildenafil in patients receiving ritonavir. Co-administration of ritonavir with sildenafil is expected to substantially increase sildenafil inhibitor concentrations (11-fold increase in AUC) and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes, and prolonged erection (see WARNINGS and PRECAUTIONS: Drug Interactions , Table 3: Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies and the complete prescribing information for sildenafil).
Concomitant use of ritonavir with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including ritonavir, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg atorvastatin or cerivastatin) The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir are used in combination with these drugs.
Concomitant use of ritonavir and St John`s wort ( Hypericum perforatum ) or products containing St John`s wort is not recommended. Co-administration of protease inhibitors, including ritonavir with St Johns wort, is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of ritonavir and lead to loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors.
Table 2: Drugs that should not be Co-administered with Ritonavir
| Drug Class: Drug Name |
Clinical Comment |
| Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
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| Antihistamines: astemizole, terfenadine |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Ergot Derivatives: dihydroergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. |
| GI motility agent: cisapride |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Herbal Products: St. John`s wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to Ritonavir or to the class of protease inhibitors. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias |
| Sedative/hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
Pregnancy
Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.
Lactation
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ritonavir is administered to a woman who is nursing . However, it is advised that HIV-infected women do not breast-feed to avoid postnatal transmission of HIV to their infants who may not be infected.
Pediatric Use
The safety and pharmacokinetic profile of ritonavir in pediatric patients below the age of 2 years have not been established. In HIV-infected patients aged 2 to 16 years, the adverse event profile appears to be similar to that for adult patients.
UNDESIRABLE EFFECTS
Overall the most frequently reported clinical adverse events, other than asthenia, among patients receiving ritonavir were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias.
Adverse events occurring in less than 2% of patients receiving ritonavir in all phase II/phase III studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.
Body as a Whole : Abdomen enlarged, accidental injury, allergic reaction, back pain, cachexia, chest pain, chills, facial edema, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and substernal chest pain.
Cardiovascular System : Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia and vasospasm.
Digestive System : Abnormal stools, bloody diarrhoea, cheilitis, cholestatic jaundice, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, ileus, liver damage, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue oedema, and ulcerative colitis.
Endocrine System : Adrenal cortex insufficiency and diabetes mellitus.
Hemic and Lymphatic System : Acute myeloblastic leukemia, anaemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.
Metabolic and Nutritional Disorders : Albuminuria, alcohol intolerance, avitaminosis, BUN increased, dehydration, oedema, enzymatic abnormality, glycosuria, gout, hypercholesteremia, peripheral oedema, and xanthomatosis.
Musculoskeletal System : Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, and twitching.
Nervous System : Abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, dementia, depersonalization, diplopia, emotional lability, euphoria, grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, libido decreased, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral
neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tremor, urinary retention, vertigo, and vestibular disorder.
Respiratory System : Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx oedema, lung disorder, rhinitis, and sinusitis.
Skin and Appendages : Acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, and vesiculobullous rash.
Special Senses : Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, and vitreous disorder.
Urogenital System : Acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney function abnormal, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, urinary tract infection, and vaginitis.
Post-marketing Experience:
The following adverse events 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.
Redistribution/accumulation of body fat has been reported (see WARNINGS and PRECAUTIONS, Fat Redistribution ).
Cardiovascular System : 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, primarily at higher doses, has been co-administered with fluticasone propionate.
Hemic and Lymphatic System : There have been reports of increased bleeding in patients with hemophilia A or B (see WARNINGS and PRECAUTIONS, Hemophilia)
Nervous System: There have been post-marketing reports of seizure. Also, see Cardiovascular System .
OVERDOSAGE
Acute overdosage
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/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
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 emesis or 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.
PACKAGING INFORMATION
RITOMUNE Container of 60 tablets
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