Generic Name: lopinavir and ritonavir
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Indications and Usage for Kaletra
Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with Kaletra:
- The use of other active agents with Kaletra is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14)].
- Genotypic or phenotypic testing and/or treatment history should guide the use of Kaletra [see Clinical Pharmacology (12.4)]. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to Kaletra [see Clinical Pharmacology (12.4)].
- Once daily administration of Kaletra is not recommended for any pediatric patients.
Kaletra Dosage and Administration
Kaletra tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.
Kaletra oral solution must be taken with food.
Adult Patients
- Kaletra tablets 400/100 mg (given as two 200/50 mg tablets) twice daily.
- Kaletra oral solution 400/100 mg (5 mL) twice daily.
- Kaletra tablets 800/200 mg (given as four 200/50 mg tablets) once daily in patients with less than three lopinavir resistance-associated substitutions.
- Kaletra oral solution 800/200 mg (10 mL) once daily in patients with less than three lopinavir resistance-associated substitutions.
Once daily administration of Kaletra is not recommended for adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V [see Clinical Pharmacology ( 12.4)].
Kaletra should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions (7)].
Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir or Nelfinavir
[see Clinical Pharmacology (12.3) and [Drug Interactions (7.3)]
Kaletra tablets and oral solution should not be administered as a once daily regimen in combination with efavirenz, nevirapine, amprenavir, or nelfinavir.
- A dose increase is recommended for all patients who use Kaletra tablets. The recommended dose of Kaletra tablets is 500/125 mg (such as two 200/50 tablets and one 100/25 mg tablet) twice daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
- A dose increase is recommended for all patients who use Kaletra oral solution. The recommended dose of Kaletra oral solution is 533/133 mg (6.5 mL) twice daily when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
Pediatric Patients
Kaletra tablets and oral solution should not be administered once daily in pediatric patients < 18 years of age.
Kaletra 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 42 weeks and a postnatal age of at least 14 days has been attained [see Warnings and Precautions (5.2)].
Kaletra oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dose of Kaletra, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for infants and young children. Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 14 days 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)].
Prescribers should calculate the appropriate dose of Kaletra for each individual child based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.
Body surface area (BSA) can be calculated as follows:
The Kaletra dose can be calculated based on weight or BSA:
Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)
Patient BSA (m2) × Prescribed lopinavir dose (mg/m2) = Administered lopinavir dose (mg)
If Kaletra oral solution is used, the volume (mL) of Kaletra solution can be determined as follows:
Volume of Kaletra solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)
The dose of the oral solution should be administered using a calibrated dosing syringe.
Before prescribing Kaletra 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a Kaletra tablet, the Kaletra oral solution formulation should be prescribed.
In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using Kaletra oral solution is 16/4 mg/kg or 300/75 mg/m2 twice daily. Prescribers should calculate the appropriate dose based on body weight or body surface area.
Because no data exists for dosage when administered with efavirenz, nevirapine, amprenavir, or nelfinavir, it is recommended that Kaletra not be administered in combination with these drugs in patients < 6 months of age.
Without Concomitant Efavirenz, Nevirapine, Amprenavir or Nelfinavir
Dosing recommendations using oral solution
In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using Kaletra oral solution without concomitant efavirenz, nevirapine, amprenavir, or nelfinavir is 230/57.5 mg/m2 given twice daily, not to exceed the recommended adult dose (400/100 mg [5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.
Dosing recommendations using tablets
Table 1 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for Kaletra tablets.
| Body Weight (kg) | Body Surface Area (m2)* | Recommended number of 100/25 mg Tablets Twice Daily |
| 15 to 25 | ≥0.6 to < 0.9 | 2 |
| >25 to 35 | ≥0.9 to < 1.4 | 3 |
| >35 | ≥1.4 | 4 (or two 200/50 mg tablets) |
| * Kaletra oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet. | ||
Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir, or Nelfinavir
Dosing recommendations using oral solution
A dose increase of Kaletra to 300/75 mg/m2 using Kaletra oral solution is needed when co-administered with efavirenz, nevirapine, amprenavir, or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose (533/133 mg [6.5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients >15 kg to 45 kg is 11/2.75 mg/kg given twice daily.
Dosing recommendations using tablets
Table 2 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for Kaletra tablets when given in combination with efavirenz, nevirapine, amprenavir, or nelfinavir.
| Body Weight (kg) | Body Surface Area (m2)* | Recommended number of 100/25 mg Tablets Twice Daily |
| 15 to 20 | ≥0.6 to < 0.8 | 2 |
| >20 to 30 | ≥0.8 to < 1.2 | 3 |
| >30 to 45 | ≥1.2 to <1.7 | 4 (or two 200/50 mg tablets) |
| >45 | ≥1.7 | 5 [see Dosage and Administration, Adult Patients (2.1)] |
| * Kaletra oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet. † Please refer to the individual product labels for appropriate dosing in children. | ||
Dosage Forms and Strengths
- Kaletra Tablets, 200 mg lopinavir/50 mg ritonavir
Yellow, film-coated, ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo-Code KA providing 200 mg lopinavir/50 mg ritonavir. - Kaletra Tablets, 100 mg lopinavir/25 mg ritonavir
Pale yellow, film-coated, ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo-Code KC providing 100 mg lopinavir/25 mg ritonavir. - Kaletra Oral Solution
Light yellow to orange colored liquid containing 400 mg lopinavir/100 mg ritonavir per 5 mL (80 mg lopinavir/20 mg ritonavir per mL).
Contraindications
- Kaletra is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) to any of its ingredients, including ritonavir.
- Co-administration of Kaletra is 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.
- Co-administration of Kaletra is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. These drugs are listed in Table 3.
| Drug Class | Drugs Within Class That Are Contraindicated With Kaletra | Clinical comments |
| Alpha 1- Adrenoreceptor antagonist | Alfuzosin | Potentially increased alfuzosin concentrations can result in hypotension. |
| Antimycobacterial | Rifampin | May lead to loss of virologic response and possible resistance to Kaletra or to the class of protease inhibitors or other co-administered antiretroviral agents [see Drug Interactions (7)]. |
| Ergot Derivatives | Dihydroergotamine, ergonovine, ergotamine, methylergonovine | Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI motility agent | Cisapride | Potential for cardiac arrhythmias. |
| Herbal Products | St. John's Wort (hypericum perforatum) | May lead to loss of virologic response and possible resistance to Kaletra or to the class of protease inhibitors. |
| HMG-CoA Reductase Inhibitors | Lovastatin, simvastatin | Potential for myopathy including rhabdomyolysis. |
| PDE5 enzyme inhibitor | Sildenafila (Revatio®) when used for the treatment of pulmonary arterial hypertension | A safe and effective dose has not been established when used with Kaletra. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Drug Interactions (7)]. |
| Neuroleptic | Pimozide | Potential for cardiac arrhythmias. |
| Sedative/Hypnotics | Triazolam; orally administered midazolamb | Prolonged or increased sedation or respiratory depression. |
| a see Drug Interactions (7) for coadministration of sildenafil in patients with erectile dysfunction. bsee Drug Interactions, Table 9 for parenterally administered midazolam. | ||
Warnings and Precautions
Drug Interactions - CYP3A Enzyme Inhibition
Kaletra is a CYP3A inhibitor. Initiating treatment with Kaletra in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on Kaletra may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with Kaletra. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with Kaletra.
See Tables 3 and 9 for listing of drugs that are contraindicated for use with Kaletra due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity [see Contraindications (4) and Drug Interactions (7)].
Toxicity in Preterm Neonates
Kaletra oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra oral solution.
Kaletra oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of Kaletra oral solution in this patient population has not been established. However, if the benefit of using Kaletra oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to Kaletra oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see Dosage and Administration (2.2) and Overdosage (10)].
Pancreatitis
Pancreatitis has been observed in patients receiving Kaletra therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Kaletra has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis [see Warnings and Precautions (5.10)]. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during Kaletra therapy.
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 occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra and/or other antiretroviral therapy should be suspended as clinically appropriate.
Hepatotoxicity
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of Kaletra.
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with Kaletra therapy has not been established.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of Kaletra in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with Kaletra therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with Kaletra and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of Kaletra treatment [see Use In Specific Populations (8.6)].
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 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.
PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. Kaletra should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of Kaletra with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of Kaletra with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Clinical Pharmacology (12.3)].
QT Interval Prolongation
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of Kaletra could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval [see Clinical Pharmacology (12.3)].
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Kaletra. 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Lipid Elevations
Treatment with Kaletra has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating Kaletra therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with Kaletra and HMG-CoA reductase inhibitors [see Contraindications (4) and Drug Interactions (7.3)].
Patients with Hemophilia
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported 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 between protease inhibitor therapy and these events has not been established.
Resistance/Cross-resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in Kaletra-treated patients, it is unknown what effect therapy with Kaletra will have on the activity of subsequently administered protease inhibitors [see Clinical Pharmacology (12.4)].
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- PR Interval Prolongation, QT Interval Prolongation [see Warnings and Precautions (5.6, 5.7)]
- Drug Interactions [see Warnings and Precautions (5.1)]
- Pancreatitis [see Warnings and Precautions (5.3)]
- Hepatotoxicity [see Warnings and Precautions (5.4)]
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.
Adults - Clinical Trials Experience
The safety profile of Kaletra in adults is primarily based on 1964 HIV-1 infected patients in clinical trials.
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. In study 730, the incidence of diarrhea of any severity during 48 weeks of therapy was 60% in patients receiving Kaletra tablets once daily compared to 57% in patients receiving Kaletra tablets twice daily. More patients receiving Kaletra tablets once daily (14, 4.2%) had ongoing diarrhea at the time of discontinuation as compared to patients receiving Kaletra tablets twice daily (6, 1.8%). In study 730, discontinuations due to any adverse reaction were 4.8% in patients receiving Kaletra tablets once daily as compared to 3% in patients receiving Kaletra tablets twice daily. In study 802, the incidence of diarrhea of any severity during 48 weeks of therapy was 50% in patients receiving Kaletra tablets once daily compared to 39% in patients receiving Kaletra tablets twice daily. Moderate or severe drug-related diarrhea occurred in 14% of patients receiving Kaletra tablets once daily as compared to 11% in patients receiving Kaletra tablets twice daily. At the time of discontinuation, 19 (6.3%) patients receiving Kaletra tablets once daily had ongoing diarrhea, as compared to 11 (3.7%) patients receiving Kaletra tablets twice daily. Discontinuations due to any adverse reaction occurred in 4.3% of patients receiving Kaletra tablets once daily compared to 7.0% in patients receiving Kaletra tablets twice daily. In study 863, discontinuations of randomized therapy due to adverse reactions were 3.4% in Kaletra-treated and 3.7% in nelfinavir-treated patients.
Treatment-emergent clinical adverse reactions of moderate or severe intensity in ≥ 2% of patients treated with combination therapy for up to 48 weeks (Studies 863 and 730) and for up to 360 weeks (Study 720) are presented in Table 4 (treatment-naïve patients); and for up to 48 weeks (Studies 888 and 802), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 5 (protease inhibitor-experienced patients).
| Study 863 (48 Weeks) | Study 720 (360 Weeks) | Study 730 (48 Weeks) | |||
| Kaletra 400/100 mg Twice Daily + d4T + 3TC (N = 326) | Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) | Kaletra Twice Daily2 + d4T + 3TC (N = 100) | Kaletra 800/200 mg Once Daily + TDF +FTC (N=333) | Kaletra 400/100 mg Twice Daily + TDF +FTC (N=331) | |
| Endocrine Disorders | |||||
| Hypogonadism | 0% | 0% | 2% | 0% | 0% |
| Gastrointestinal Disorders | |||||
| Diarrhea | 16% | 17% | 28% | 17% | 15% |
| Nausea | 7% | 5% | 16% | 7% | 5% |
| Vomiting | 2% | 2% | 6% | 3% | 4% |
| Abdominal Pain | 4% | 3% | 11% | 1% | 1% |
| Dyspepsia | 2% | <1% | 6% | 0% | 0% |
| Flatulence | 2% | 1% | 4% | 1% | 1% |
| General Disorders and Administration Site Conditions | |||||
| Asthenia | 4% | 3% | 9% | <1% | <1% |
| Infections and Infestations | |||||
| Bronchitis | 0% | 0% | 2% | 0% | <1% |
| Investigations | |||||
| Weight decreased | 1% | <1% | 2% | 0% | <1% |
| Metabolism and Nutrition Disorders | |||||
| Anorexia | 1% | <1% | 2% | <1% | 1% |
| Musculoskeletal and Connective Tissue Disorders | |||||
| Myalgia | 1% | 1% | 2% | 0% | 0% |
| Nervous System Disorders | |||||
| Headache | 2% | 2% | 6% | 2% | 2% |
| Paresthesia | 1% | 1% | 2% | 0% | 0% |
| Psychiatric Disorders | |||||
| Insomnia | 2% | 1% | 3% | 1% | 0% |
| Depression | 1% | 2% | 0% | 0% | 0% |
| Libido decreased | <1% | <1% | 2% | 0% | <1% |
| Skin and Subcutaneous Tissue Disorders | |||||
| Rash | 1% | 2% | 5% | <1% | 1% |
| Vascular Disorders | |||||
| Vasodilation | 0% | 0% | 3% | 0% | 0% |
| 1 Includes adverse reactions of possible or probable relationship to study drug. 2 Includes adverse reaction data from dose group I (200/100 mg twice daily [N = 16] and 400/100 mg twice daily [N = 16]) and dose group II (400/100 mg twice daily [N = 35] and 400/200 mg twice daily [N = 33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to Kaletra occurred at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II. Definitions: d4T = Stavudine; 3TC = Lamivudine; TDF = Tenofovir Disoproxil Fumarate; FTC = Emtricitabine | |||||
| Study 888 (48 Weeks) | Study 9572 and Study 7653 (84-144 Weeks) | Study 802 (48 Weeks) | |||
| Kaletra 400/100 mg Twice Daily + NVP + NRTIs (N = 148) | Investigator-selected protease inhibitor(s) + NVP + NRTIs (N = 140) | Kaletra Twice Daily + NNRTI + NRTIs (N = 127) | Kaletra 800/200 mg Once Daily +NRTIs (N=300) | Kaletra 400/100 mg Twice Daily + NRTIs (N=299) | |
| Gastrointestinal Disorders | |||||
| Diarrhea | 7% | 9% | 23% | 14% | 11% |
| Nausea | 7% | 16% | 5% | 3% | 7% |
| Vomiting | 4% | 12% | 2% | 2% | 3% |
| Abdominal Pain | 2% | 2% | 4% | 2% | <1% |
| Abdominal Pain Upper | N/A | N/A | N/A | 1% | 2% |
| Dyspepsia | 1% | 1% | 2% | 1% | <1% |
| Flatulence | 1% | 2% | 2% | 1% | 1% |
| Dysphasia | 2% | 1% | 0% | 0% | 0% |
| General Disorders and Administration Site Conditions | |||||
| Asthenia | 3% | 6% | 9% | <1% | <1% |
| Pyrexia | 2% | 1% | 2% | 0% | <1% |
| Chills | 2% | 0% | 0% | 0% | 0% |
| Investigations | |||||
| Weight decreased | 0% | 1% | 3% | <1% | <1% |
| Metabolism and Nutrition Disorders | |||||
| Anorexia | 1% | 3% | 0% | 0% | 1% |
| Musculoskeletal and Connective Tissue Disorders | |||||
| Myalgia | 1% | 1% | 2% | 0% | 0% |
| Nervous System Disorders | |||||
| Headache | 2% | 3% | 2% | <1% | 0% |
| Paresthesia | 0% | 1% | 2% | 0% | 0% |
| Psychiatric Disorders | |||||
| Depression | 1% | 2% | 3% | <1% | 0% |
| Insomnia | 0% | 2% | 2% | 0% | <1% |
| Skin and Subcutaneous Tissue Disorders | |||||
| Rash | 2% | 1% | 2% | 0% | 0% |
| Vascular Disorders | |||||
| Hypertension | 0% | 0% | 2% | 0% | |
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